Atreca Inc (BCEL) 2022 Q4 法說會逐字稿

Thank you for standing by, and welcome to Atreca's fourth-quarter and year-end 2022 earnings call. (Operator Instructions)

感謝您的耐心等待，歡迎參加 Atreca 第四季度和 2022 年年底的財報電話會議。 （操作員說明）

I would now like to hand the call over to Head of Investor Relations, Alex Gray. Please go ahead.

我現在想將電話轉給投資者關係主管 Alex Gray。請繼續。

Thank you, operator, and thank you to those joining us today. We are pleased to host our year-end 2022 conference call and webcast, including updated data from our ongoing Phase 1b trial of ATRC-101. Joining me for the prepared remarks are John Orwin, CEO; Dr. Tito Serafini, Chief Strategy Officer and Atreca Founder; Dr. Philippe Bishop, Chief Medical Officer; and Dr. Stephen Gould, Chief Scientific Officer. Also on the line is Herb Cross, Chief Financial Officer, who will be available during the Q&A session.

謝謝您，接線員，也謝謝今天加入我們的人。我們很高興舉辦 2022 年年底電話會議和網絡廣播，其中包括我們正在進行的 ATRC-101 1b 期試驗的最新數據。與我一起發表準備好的講話的是首席執行官 John Orwin； Tito Serafini 博士，首席戰略官兼 Atreca 創始人； Philippe Bishop 博士，首席醫療官；和首席科學官斯蒂芬·古爾德博士。首席財務官赫伯·克羅斯 (Herb Cross) 也在線上，他將出席問答環節。

For those joining by phone, I'd note that we are presenting slides as part of today's program, which can be viewed via the webcast link included in our earnings release and posted to the Events and Presentations section of our Investor Relations website at ir.atreca.com. An archived replay of today's webcast and the accompanying slides will be available on our IR site following the live presentation.

對於那些通過電話參加的人，我要指出的是，我們將在今天的計劃中展示幻燈片，您可以通過我們的收益發布中包含的網絡廣播鏈接觀看這些幻燈片，並將其發佈到我們投資者關係網站 ir 的活動和演示部分。 atreca.com。現場演示結束後，我們的 IR 網站將提供今天網絡廣播的存檔重播以及隨附的幻燈片。

During today's call, we will be making forward-looking statements based on current expectations. These statements are subject to a number of significant risks and uncertainties, and our actual results may differ materially. For a description of risks and factors that could affect our future financial results and business, please refer to the disclosure in the accompanying slides, our most recent Forms 10-K and 10-Q, and the report that we may file on Form 8-K with the Securities and Exchange Commission.

在今天的電話會議中，我們將根據當前預期做出前瞻性聲明。這些陳述面臨許多重大風險和不確定性，我們的實際結果可能存在重大差異。有關可能影響我們未來財務業績和業務的風險和因素的描述，請參閱隨附幻燈片、我們最新的表格 10-K 和 10-Q 以及我們可能在表格 8- 上提交的報告中的披露K 與證券交易委員會。

Our statements are made as of today, March 29, 2023, based on information currently available to us. We can give no assurance that these statements will prove to be correct. We undertake no duty to update these statements except as required by law.

我們的聲明是根據我們目前掌握的信息於今天（2023 年 3 月 29 日）作出的。我們不能保證這些陳述將被證明是正確的。除法律要求外，我們不承擔更新這些聲明的義務。

I'll now turn it over to John Orwin. John?

我現在將把它交給約翰·奧爾文。約翰？

Thank you, Alex. On today's call, Tito will provide an update on our discovery platform and its evolution. Philippe will present data from the ATRC-101 monotherapy pembrolizumab combination cohorts in our ongoing Phase 1b trial, and Stephen will then provide an overview of our preclinical pipeline. I will then discuss our financials and upcoming milestones before opening the line for Q&A.

謝謝你，亞歷克斯。在今天的電話會議上，蒂托將提供有關我們的發現平台及其演變的最新信息。 Philippe 將介紹我們正在進行的 1b 期試驗中 ATRC-101 單藥療法 pembrolizumab 組合隊列的數據，然後 Stephen 將概述我們的臨床前產品線。然後，在開通問答熱線之前，我將討論我們的財務狀況和即將到來的里程碑。

Shown on slide 4 is a broad overview of our platform and pipeline. As a reminder, Atreca has a proprietary platform that enables us to access novel antibodies binding to novel tumor targets that would unlikely be found via traditional discovery approach. As Tito will discuss in more detail, we have continued to invest in the development of the platform, which has enabled us to find promising antibodies and identify their targets more efficient.

第 4 張幻燈片顯示了我們的平台和管道的總體概述。提醒一下，Atreca 擁有一個專有平台，使我們能夠獲得與新腫瘤靶點結合的新抗體，而通過傳統的發現方法不太可能發現這些靶點。正如 Tito 將更詳細討論的那樣，我們繼續投資該平台的開發，這使我們能夠找到有前途的抗體並更有效地識別其目標。

From a platform, we've generated robust pipeline led by ATRC-101, which as we'll discuss later, has demonstrated durable antitumor activity in the ongoing Phase 1b trial and which we believe validates the ability of our platform to identify active tumor targeting antibodies with therapeutic potential. We plan to provide an update on our clinical strategy for ATRC-101, including a go/no-go decision for Phase 2 development by the end of this year.

通過一個平台，我們已經生成了以 ATRC-101 為主導的強大產品線，正如我們稍後將討論的，它在正在進行的 1b 期試驗中證明了持久的抗腫瘤活性，我們相信這驗證了我們的平台識別主動腫瘤靶向的能力具有治療潛力的抗體。我們計劃在今年年底前提供 ATRC-101 臨床策略的最新信息，包括進行/不進行 2 期開發的決定。

We are also advancing multiple promising preclinical programs, including APN-497444, which targets a novel tumor-specific ligand and is advancing at an antibody drug conjugate, as well as APN-346958, which recognizes the cell surface RNA-binding protein target and is advancing as a T cell engager in partnership with Xencor. We expect to nominate clinical candidates from both programs later this year and begin clinical studies for additional oncology programs in 2025.

我們還在推進多個有前景的臨床前項目，包括 APN-497444（針對新型腫瘤特異性配體，正在開發抗體藥物綴合物）以及 APN-346958（識別細胞表面 RNA 結合蛋白靶標，並正在開發）。與 Xencor 合作，作為 T 細胞參與者不斷進步。我們預計將在今年晚些時候提名這兩個項目的臨床候選人，並於 2025 年開始其他腫瘤學項目的臨床研究。

I will now turn it over to Tito to briefly discuss our discovery platform and its evolution before we review the updated ATRC-101 data and preclinical pipeline.

現在，我將把它交給 Tito，在我們審查更新的 ATRC-101 數據和臨床前管道之前，簡要討論我們的發現平台及其演變。

Thanks, John. On slide 5, our pipeline is generated by an approach in which the active immune response guides us to novel antibodies, finding novel targets. On the top half of the slide, starting on the left, our approach begins with blood samples from patients whose adaptive immune system is attacking tumor tissue.

謝謝，約翰。在幻燈片 5 上，我們的管道是通過主動免疫反應引導我們開發新抗體、尋找新靶標的方法生成的。在幻燈片的上半部分，從左側開始，我們的方法從適應性免疫系統正在攻擊腫瘤組織的患者的血液樣本開始。

Moving to the right, via those samples, we access that immune response, and importantly, the active immune response by analyzing single B cells of a defined type to generate a high fidelity to natively pair heavy and light chains of the antibodies that are being generated in that patient at that point in time.

向右移動，通過這些樣本，我們可以獲取免疫反應，更重要的是，通過分析特定類型的單個 B 細胞來生成與正在生成的抗體的天然配對重鍊和輕鏈的高保真度，從而獲得主動免疫反應在那個時間點那個病人身上。

Moving again to the right, we then analyze and select those antibody sequences in silico for synthesis and further evaluation in the laboratory. By screening the synthesized antibodies in vitro, we ask a simple question, does this antibody, which comes from the immune response of one patient, bind to tumor tissue of other patients that is not autologous tumor tissue and does it do so preferentially over normal tissue? If the answer is yes and the antibody also binds to the surface of a tumor cell line as measured by flow cytometry, we have a hit antibody.

再次向右移動，然後我們在計算機中分析並選擇這些抗體序列，以便在實驗室中合成和進一步評估。通過體外篩選合成的抗體，我們提出一個簡單的問題，這種來自一名患者免疫反應的抗體是否會與其他患者的非自體腫瘤組織的腫瘤組織結合，並且是否比正常組織更優先結合？如果答案是肯定的，並且通過流式細胞術測量抗體也與腫瘤細胞系的表面結合，那麼我們就有了命中抗體。

On the bottom half of the slide, we then further evaluate and develop our hit antibodies in order to turn them into clinical candidates as I'll describe in a moment in more detail.

在幻燈片的下半部分，我們進一步評估和開發我們的命中抗體，以便將它們轉變為臨床候選藥物，我將在稍後更詳細地描述。

Moving to slide 6, this slide illustrates the biology behind why our approach works. The key point of this slide is that we generate antibodies from plasma blast, those four B cells in the middle of the figure. Plasma blasts uniquely provide information on the antigens being processed and the antibody being generated during an active immune response.

轉到幻燈片 6，這張幻燈片說明了我們的方法有效背後的生物學原理。這張幻燈片的關鍵點是我們從血漿母細胞（圖中間的四個 B 細胞）中產生抗體。等離子爆炸獨特地提供了有關正在處理的抗原和主動免疫反應期間生成的抗體的信息。

In the blow-up we're showing as dots, antibodies generated a two time points from one patient before treatment in purple and after treatment in green. And we've circled groups of dots, these groups of plasma blast antibodies are clonal families derived from a single progenitor B cell. And these particular families, colored green, regenerated in this case, is the patient was successfully attacking his tumor tissue to yield a partial response.

在我們以點形式顯示的放大圖中，一名患者在治療前（紫色）和治療後（綠色）產生了兩個時間點的抗體。我們圈出了一組點，這些漿母細胞抗體組是源自單個 B 祖細胞的克隆家族。這些特殊的家族，呈綠色，在這種情況下再生，是患者成功攻擊他的腫瘤組織以產生部分反應。

By analyzing clonal families such as these, their appearance, persistence, disappearance, size, all of that enabled by our approach, as well as by analyzing antibody sequences more directly, we focus on and select particular antibodies for further evaluation in the laboratory. Our in silico analysis deliver synthesized antibodies, binding non-autologous tumor tissue, approximately 50% of the time in our primary screens.

通過分析諸如此類的克隆家族，它們的出現、持久性、消失、大小，所有這些都是通過我們的方法實現的，以及通過更直接地分析抗體序列，我們專注於並選擇特定的抗體以在實驗室中進行進一步評估。我們的計算機分析提供合成的抗體，結合非自體腫瘤組織，在我們的初步篩選中大約有 50% 的時間。

And as noted at the bottom of this slide, our proprietary approach is protected by composition of matter claims in multiple jurisdictions worldwide, which goes beyond the more typical method of use claims often granted around processes.

正如本幻燈片底部所指出的，我們的專有方法受到全球多個司法管轄區的物質組合聲明的保護，這超出了通常圍繞流程授予的更典型的使用方法聲明。

Moving to slide 7, this is the discovery platform that we have built in over a decade to execute on our approach. I'll focus on a few key points. Starting on the left, we run our own non-interventional studies in order to acquire samples from cancer patients, and we have generated a valuable sample repository now with over 1,700 clinically annotated samples from over 500 donors, representing nearly 40 tumor types.

轉向幻燈片 7，這是我們十多年來建立的發現平台，用於執行我們的方法。我將重點討論幾個關鍵點。從左邊開始，我們進行自己的非干預性研究，以便從癌症患者那裡獲取樣本，我們現在已經生成了一個有價值的樣本庫，其中包含來自 500 多名捐贈者的 1,700 多個臨床註釋樣本，代表近 40 種腫瘤類型。

Moving right, I briefly described that we use these samples to generate, analyze, and select plasma blasts antibodies for analysis by histology and flow cytometry to generated antibodies. And then moving further right, turning these hit antibodies into leads requires their evaluation in vitro for tumoricidal activity but in a manner that provides information about which weaponization would be most suitable. And then with the active antibody enhanced that also has positive histology data, we work to identify the target bound by the antibody and eventually lead itself on that target.

向右移動，我簡要描述了我們使用這些樣本來生成、分析和選擇血漿母細胞抗體，以便通過組織學和流式細胞術進行分析以生成抗體。然後進一步向右移動，將這些命中抗體轉化為先導化合物，需要對其殺腫瘤活性進行體外評估，但要以提供有關哪種武器化最合適的信息的方式進行評估。然後，隨著活性抗體的增強且具有陽性組織學數據，我們致力於識別抗體結合的靶標，並最終引導自身到達該靶標。

Moving further right again, if an antibody meets our criteria, we then work to generate a clinical candidate from that antibody by engineering a final weaponized format and optimizing its sequence by assuring a suitable safety profile and by identifying biomarkers suitable for use during clinical development.

再進一步，如果抗體符合我們的標準，我們就會通過設計最終的武器化形式並通過確保合適的安全性和識別適合在臨床開發過程中使用的生物標誌物來優化其序列，從而從該抗體中生成臨床候選藥物。

Moving to slide 8, as we promised to do, we've evolved the platform over time to achieve greater efficiency in delivering pipeline assets. On this slide, I'm highlighting a few of the more salient advances that we've made. Starting in the top left, we've expanded our sample collection to new sites and indications. Moving down, we're operating our flow cytometry now at an industrial scale and speed. And below that, our histological analysis has now incorporated more automation to enable earlier evaluation of tumor and normal tissue expression of our antibody targets.

轉到幻燈片 8，正如我們所承諾的那樣，我們隨著時間的推移不斷改進該平台，以實現更高的管道資產交付效率。在這張幻燈片上，我強調了我們取得的一些更顯著的進步。從左上角開始，我們將樣本收集擴展到新的位點和適應症。接下來，我們現在正在以工業規模和速度運行我們的流式細胞術。在此之下，我們的組織學分析現已融入更多自動化功能，以便能夠更早地評估我們抗體靶點的腫瘤和正常組織表達。

Moving to the top right, we've implemented proprietary, high-throughput assays to measure in vitro the activity relevant to weaponization. Next down, whole genome functional genomic screens were added to existing biochemical methods to remove a bottleneck that target identification that's represented in our platform. And finally, but again, not exclusively, we've implemented structure-based and unbiased lead optimization to generate candidates in multiple weaponization format.

轉到右上角，我們實施了專有的高通量測定，以在體外測量與武器化相關的活動。接下來，將全基因組功能基因組篩選添加到現有的生化方法中，以消除我們平台中代表的目標識別的瓶頸。最後，但同樣，不僅僅是，我們實施了基於結構和無偏見的先導優化，以生成多種武器化格式的候選藥物。

Moving to slide 9, we'll quickly review our current pipeline, all the assets of which have been generated by our platform. On slide 10, you see a listing of our clinical and later-stage preclinical assets such as our clinical-stage asset, ATRC-101, which Philippe will discuss in detail. You'll then hear from Stephen about the other currently preclinical pipeline assets.

轉到幻燈片 9，我們將快速回顧一下當前的管道，其中所有資產都是由我們的平台生成的。在幻燈片 10 上，您可以看到我們的臨床和後期臨床前資產的列表，例如我們的臨床階段資產 ATRC-101，Philippe 將詳細討論該資產。然後，您將聽到 Stephen 關於其他當前臨床前管道資產的信息。

Turning it over to Philippe.

把它交給菲利普。

Thanks, Tito, and thank you, everyone, for joining the call today. On slide 12 is a topline summary of ATRC-101 Phase 1b study update I am presenting today, which includes inflammation from 71 patients treated in the ongoing trial, 21 of them were enrolled since our March 2022 update. The primary objective of the study is to evaluate safety, and we're pleased to share that ATRC-101 continues to be well tolerated in the monotherapy and combination arms, including at the highest dose level of 30 milligram per kilogram.

謝謝蒂托，也謝謝大家今天加入電話會議。第 12 張幻燈片是我今天介紹的 ATRC-101 1b 期研究更新的頂線摘要，其中包括正在進行的試驗中治療的 71 名患者的炎症，其中 21 名患者是自 2022 年 3 月更新以來入組的。該研究的主要目的是評估安全性，我們很高興地告訴大家，ATRC-101 在單一療法和聯合療法中仍然具有良好的耐受性，包括在每公斤 30 毫克的最高劑量水平下。

We continue to see anti-tumor activity in patients that express target. Furthermore, we're excited to report that in this heterogeneous and heavily pretreated participant group, we are seeing durable responses and stable disease across several cancer types in participants treated with monotherapy and combination therapy.

我們繼續看到表達靶點的患者俱有抗腫瘤活性。此外，我們很高興地報告，在這個異質且經過大量預處理的參與者群體中，我們看到接受單一療法和聯合療法治療的參與者對幾種癌症類型的持久反應和穩定的疾病。

Before we discuss the data, I will briefly review the trial design, the baseline characteristics of participants treated and the analysis set in the next three slides. As a reminder, and as shown on slide 13, this is a basket trial enrolling patients across multiple tumor types. The primary objective of the trial is to determine the safety and tolerability for the ATRC-101 when administered as monotherapy or in combination, with key additional objectives, including measuring clinical activity, analyzing target expression, determining indications for expansion.

在我們討論數據之前，我將簡要回顧一下試驗設計、接受治療的參與者的基線特徵以及接下來三張幻燈片中的分析集。提醒一下，如幻燈片 13 所示，這是一項納入多種腫瘤類型患者的籃子試驗。該試驗的主要目的是確定 ATRC-101 作為單一療法或聯合用藥時的安全性和耐受性，以及其他關鍵目標，包括測量臨床活性、分析靶標表達、確定擴展適應症。

The trial began with ATRC-101 administered as monotherapy every three or two weeks, followed by studying the combination with pembrolizumab every three weeks in patients who had progressed, or in the opinion of the treating physician, achieved an unsatisfactory response following an anti-PD-1 or PD-L1 therapy. The initial dose escalation cohort included patients regardless of target expression.

該試驗開始時每三週或兩週進行一次 ATRC-101 單藥治療，隨後每三週對病情進展的患者或治療醫生認為在抗 PD 治療後療效不佳的患者中研究與派姆單抗的聯合治療-1或PD-L1治療。初始劑量遞增隊列包括患者，無論靶標表達如何。

Last year, when early data suggested a target expression appeared to discriminate patients likely to respond, we amended the protocol and started to enrich based on target expression. To date, we have treated participants at five dose levels ranging from 0.3 to 30 milligram per kilogram. Having completed the dose escalation phases of the trial, we're now expanding enrollment at 30 milligram per kilogram every three-week dose level for both monotherapy and combination cohorts.

去年，當早期數據表明目標表達似乎會歧視可能有反應的患者時，我們修改了方案並開始根據目標表達進行豐富。迄今為止，我們已對參與者進行了五種劑量水平的治療，劑量範圍為每公斤 0.3 至 30 毫克。完成試驗的劑量遞增階段後，我們現在將單藥治療和聯合治療組的入組人數擴大到每三週 30 毫克/公斤的劑量水平。

Slide 14 is an overview of the baseline characteristics of participants enrolled onto study. As of the data cutoff of February 17, 2023, 71 participants had enrolled overall, with 48 on the three-week monotherapy schedule, 14 on a two-week monotherapy schedule, and 9 in the combination arm. The median age of participants was 62 years with most having an ECOG performance status of 1.

幻燈片 14 概述了參與研究的參與者的基線特徵。截至 2023 年 2 月 17 日數據截止，共有 71 名參與者入組，其中 48 名參與者接受為期三週的單一治療方案，14 名參與者接受為期兩週的單一治療方案，9 名參與者接受聯合治療。參與者的中位年齡為 62 歲，大多數人的 ECOG 體能狀態為 1。

You can see how patients enrolled in the study are distributed across cancer types. It is very important to note that the majority of participants enrolled in the study had metastatic disease and were heavily pretreated with a median of 5 prior line of therapy.

您可以看到參與研究的患者在不同癌症類型中的分佈情況。值得注意的是，參加該研究的大多數參與者患有轉移性疾病，並且接受了中位數為 5 線的前期治療。

Nearly half of the patients had prior exposure to one or more checkpoint inhibitor. And for those enrolled onto the combination arm, as per protocol, all patients had to have received prior therapy with PD-1 or PD-L1 agent and experienced an unsatisfactory response or disease progression following treatment.

近一半的患者之前曾接觸過一種或多種檢查點抑製劑。對於那些納入聯合治療組的患者，根據方案，所有患者都必須事先接受過 PD-1 或​​ PD-L1 藥物治療，並且在治療後出現不令人滿意的反應或疾病進展。

On slide 15, I would like to describe the pertinent data sets used in today's presentation. Beginning with safety, today's results will include all 71 participants enrolled on the study who received at least one dose of ATRC-101. Although we studied five dose levels, we consider pharmacologically relevant doses to be at 3, 10, and 30 milligram per kilogram either as a monotherapy or in combination with pembrolizumab. Participant treated at these doses will be the focus of the interim analysis for activity presented today.

在幻燈片 15 上，我想描述今天演示中使用的相關數據集。從安全性出發，今天的結果將包括參與該研究的所有 71 名至少接受一劑 ATRC-101 的參與者。儘管我們研究了五個劑量水平，但我們認為藥理學相關劑量為每公斤 3、10 和 30 毫克，無論是作為單一療法還是與派姆單抗聯合用藥。以這些劑量治療的參與者將成為今天提出的活動中期分析的重點。

With these analysis, there are 62 patients with a large number enrolled at the 30 milligram per kilogram dose. Of the 62 subjects, 50 were evaluable for H-score that is defined as a composite score comprised of target expression intensity by immunohistochemistry and the proportion of cells positive for target expression. When examining target expression correlations to clinical activity, we will focus on the 45 who were evaluable for RECIST and H-score, and the 49 who were evaluable for best overall response and target expression. For these results, we will present the monotherapy results separately from the overall population that include nine individuals who received combination therapy.

通過這些分析，有 62 名大量患者參加了 30 毫克/公斤劑量的治療。在 62 名受試者中，有 50 名受試者可進行 H 評分評估，H 評分定義為由免疫組織化學測定的靶表達強度和靶表達陽性細胞比例組成的綜合評分。在檢查靶標表達與臨床活動的相關性時，我們將重點關注可評估 RECIST 和 H 評分的 45 名患者，以及可評估最佳總體反應和靶標表達的 49 名患者。對於這些結果，我們將與包括九名接受聯合治療的個體在內的總體人群分開展示單一療法的結果。

Presented on slide 16 is a distribution of participant assessable for overall response and H-score by cancer type. As you can see, the number of subjects enrolled with specific tumor types ranged from 18 to zero. As such, the small numbers make it difficult for conclusive inferences about ATRC-101 activity for a specific cancer type or indication. And although we are getting close to sufficient numbers in some of the tumor types, we believe it is important to continue enrollment of the study to provide additional insight and inform future development decisions.

幻燈片 16 中呈現的是可根據癌症類型評估總體反應和 H 評分的參與者分佈。正如您所看到的，患有特定腫瘤類型的受試者人數從 18 到 0 不等。因此，數量較少使得很難對特定癌症類型或適應症的 ATRC-101 活性做出結論性推斷。儘管我們在某些​​腫瘤類型中已接近足夠的數量，但我們認為繼續招募該研究以提供更多見解並為未來的開發決策提供信息非常重要。

Moving to slide 17, ATRC continues to be well tolerated. With the 71 participants enrolled and who received at least one dose of ATRC-101, most of the reported adverse events were Grade 1 or 2, as shown by the dark blue bars for the treatment-emergent adverse events on the left and the treatment-related adverse events on the right.

轉到幻燈片 17，ATRC 仍然具有良好的耐受性。在 71 名參加者至少接受一劑 ATRC-101 的情況下，大多數報告的不良事件都是 1 級或 2 級，如左側治療中出現的不良事件和治療中出現的不良事件的深藍色條所示。相關的不良事件在右側。

Of these adverse events observed, there remains no pattern to suggest a particular toxicity profile nor were there relationship between incidence and severity of adverse events from dose or incidence of adverse events with target expression. The most common treatment-related adverse events were pain, fatigue, and nausea with no serious adverse events determined to be related to treatment with ATRC-101.

在觀察到的這些不良事件中，仍然沒有任何模式表明特定的毒性特徵，劑量引起的不良事件的發生率和嚴重程度之間或不良事件的發生率與目標表達之間也不存在關係。最常見的治療相關不良事件是疼痛、疲勞和噁心，沒有確定與 ATRC-101 治療相關的嚴重不良事件。

Only two Grade 3 AEs were reported as potentially treatment related, including one of each of a headache and a small intestinal obstruction. 6 patients experienced an AE leading to dose interruptions. These included patients who had a Grade 2 infusion reaction on cycle one, day one. The infusion was interrupted temporarily and AE managed as per protocol. The dosing was restarted without complication.

只有兩項 3 級 AE 被報告為可能與治療相關，包括頭痛和小腸梗阻各一項。 6 名患者出現 AE，導致劑量中斷。其中包括在第一周期第一天出現 2 級輸注反應的患者。輸注暫時中斷，並按照方案處理 AE。重新開始給藥，沒有出現並發症。

Others included liver function, laboratory abnormalities, a Grade 1 tachycardia, a Grade 2 nausea, a Grade 2 fatigue, and the Grade 3 small intestinal obstruction that was noted earlier in my comments. More participants has had to come off study due to drug-related toxicity.

其他包括肝功能、實驗室異常、1 級心動過速、2 級噁心、2 級疲勞和我之前評論中提到的 3 級小腸梗阻。由於藥物相關毒性，更多參與者不得不退出研究。

Moving to slide 18, the interim assessment for activity once again supports the use of an H-score cutoff to predict the probability of observing disease control or tumor response to ATRC-101. As noted previously, the H-score is obtained using a CAP CLIA immunohistochemistry-based assay. An H-score can range from zero at the negative end to a maximum target expression score of 300. Based on prior analysis showing a correlation of H-score to response for disease control, a target positive H-score cutoff implies an H-score greater to or equal to 50.

轉到幻燈片 18，活動的中期評估再次支持使用 H 分數截止值來預測觀察疾病控製或腫瘤對 ATRC-101 反應的概率。如前所述，H 分數是使用基於 CAP CLIA 免疫組織化學的測定法獲得的。 H 分數的範圍可以從負端的零到最大目標表達分數 300。根據顯示 H 分數與疾病控制反應的相關性的先前分析，目標正 H 分數截止值意味著 H 分數大於或等於50。

On the left bar graph for patients who received monotherapy, 59% achieved disease control if their tumor expressed the target. This is in contrast to 25% of patients whose tumor has an H-score below 50. The bar graph on the right includes patients through combination therapy and yielded a similar result.

在接受單一療法的左側條形圖中，如果腫瘤表達了靶點，則 59% 的患者實現了疾病控制。這與 25% 的腫瘤 H 評分低於 50 的患者形成鮮明對比。右側的條形圖包括接受聯合治療的患者，並產生了類似的結果。

On slide 19 is another way of assessing anti-tumor activity associated with target expression. Here, we are looking at individual patient data over time for patients whose tumor has a low H-score. Those treated with monotherapy are shown on the left. And on the right, the graph also includes those treated with combination therapy.

幻燈片 19 是評估與靶標表達相關的抗腫瘤活性的另一種方法。在這裡，我們正在查看腫瘤 H 評分較低的患者隨時間變化的個體患者數據。接受單一療法治療的患者顯示在左側。右側的圖表還包括接受聯合治療的患者。

As shown here, most patients disease progression occurred early soon after the first month following initiation of protocol therapy. Only four patients had stable disease going past 100 days and all experienced disease progression at 180 days or soon thereafter.

如圖所示，大多數患者在開始方案治療後第一個月後不久就出現疾病進展。只有 4 名患者在 100 天后病情穩定，所有患者均在 180 天或此後不久出現疾病進展。

On slide 20, we compared those with low target scores in the light blue lines to those with each scores of 50 or greater in the dark blue line. And we can see that there is a greater number of patients experiencing a durable objective response or durable disease control. Several of them are well past 180 days after having initiated protocol therapy.

在幻燈片 20 上，我們將淺藍色線中目標得分較低的人與深藍色線中目標得分均為 50 或更高的人進行了比較。我們可以看到有更多的患者經歷了持久的客觀反應或持久的疾病控制。其中一些人在開始方案治療後已經過了 180 天。

In the monotherapy cohort, the bottom curve shows a patient with 40% tumor size reduction that lasted for more than 300 days. This is the patient with non-small cell lung cancer we had previously reported to have achieved a PR. That patient's tumor has an H-score of 80 and PFS was documented at study day 350. Including those who receive combination therapy on the right, we can see the melanoma patient at the bottom that we had previously reported to have achieved the CR and that patient had their most recent response assessment at day 418 following initiation protocol therapy. The patient's tumor had an H-score of 75, and to this day, continues to remain on study.

在單一療法隊列中，底部曲線顯示患者的腫瘤尺寸縮小了 40%，並持續了 300 多天。這是我們之前報導的已獲得 PR 的非小細胞肺癌患者。該患者的腫瘤 H 評分為 80，PFS 在研究第 350 天記錄。包括右側接受聯合治療的患者，我們可以在底部看到黑色素瘤患者，我們之前報告已達到 CR，並且患者在初始方案治療後第 418 天進行了最近的反應評估。該患者的腫瘤 H 評分為 75，至今仍在繼續研究中。

Slide 21 focuses on the durability of tumor response observed by cancer type for all patients treated with ATRC-101 as monotherapy or in combination with pembro and whose tumor was target positive. As shown by the different line colors depicting different cancer types, durable activity is seen across multiple tumor types, including melanoma, non-small cell lung cancer, head-and-neck cancer, colon cancer, as well as breast cancer patients who had progression-free survival documented at study day 210.

幻燈片 21 重點介紹了所有接受 ATRC-101 作為單一療法或與 pembro 聯合治療且腫瘤靶點呈陽性的患者按癌症類型觀察到的腫瘤反應的持久性。正如描繪不同癌症類型的不同線條顏色所示，多種腫瘤類型都具有持久活性，包括黑色素瘤、非小細胞肺癌、頭頸癌、結腸癌以及進展的乳腺癌患者-在研究第210天記錄無生存率。

Another way of looking at the antitumor activity by tumor type in H-score is shown in the waterfall plot on slide 22. On the left bar graph, patients with low target expression experience increase in the size of target lesions, except for one patient with ovarian cancer who had a small reduction in the size of her cancer.

在 H 評分中按腫瘤類型查看抗腫瘤活性的另一種方法如幻燈片 22 上的瀑布圖所示。在左側條形圖中，目標表達低的患者經歷目標病灶大小的增加，但一名患者除外卵巢癌患者的癌症大小略有縮小。

Patients who receive ATRC-101 alone are shown in the solid bars. Those who received combination therapy are shown in the hatched bars. This is in contrast to patients whose tumor had a higher target expression on the right bar graph. Here, we see that several patients had tumor reductions in both the monotherapy cohort, solid bars, and the combination therapy cohorts, the hatched bars.

單獨接受 ATRC-101 的患者顯示在實心條中。接受聯合治療的患者顯示在陰影條中。這與右側條形圖上腫瘤具有較高靶標表達的患者形成對比。在這裡，我們看到一些患者在單一治療組（實心條）和聯合治療組（陰影條）中腫瘤均減少。

Slide 23 is a Kaplan-Meier analysis measuring progression-free survival for patients treated as a function of H-score. On the left are the patients who received monotherapy; on the right, the Kaplan-Meier analysis includes a patient treated with monotherapy or combination therapy. Patients with an H-score of 50 or greater in the dark line have a longer progression-free survival than patients with H-score less than 50 in the blue light lines.

幻燈片 23 是 Kaplan-Meier 分析，根據 H 評分測量接受治療的患者的無進展生存期。左邊是接受單一療法的患者；右側，Kaplan-Meier 分析包括接受單一療法或聯合療法治療的患者。暗線 H 得分為 50 或更高的患者比藍光線 H 得分低於 50 的患者有更長的無進展生存期。

The curves separate early at 30 days has remained separated over time. For the monotherapy cohort, the hazard ratio of 0.47 for the difference of target positive and target negative patients. And a similar to the hazard ratio observed for all patients treated with ATRC-101, that also includes those who received combination therapy. Here, the hazard ratio is 0.4 for the difference of target positive and target negative patients.

曲線在 30 天早期分離，並隨著時間的推移保持分離。對於單一治療隊列，目標陽性和目標陰性患者差異的風險比為 0.47。與所有接受 ATRC-101 治療的患者觀察到的風險比相似，其中也包括接受聯合治療的患者。這裡，目標陽性患者和目標陰性患者之間的差異的風險比為 0.4。

Of interest are the small vertical sensor line on the curve representing patients who have not experienced an event. These patients remain on study and are still receiving protocol therapy. As you can see, some patients are past 180 days at the tail end of the dark progression-free survival curve.

令人感興趣的是曲線上代表未經歷過事件的患者的小垂直傳感器線。這些患者仍在研究中並仍在接受方案治療。正如您所看到的，一些患者已經過了 180 天，處於黑暗無進展生存曲線的末端。

Now moving to the data summary and next steps on slide 24. This is a Phase 1b trial and it has and continues to enroll patients that have, for the most part, exhausted standard of care. At this data update, ATRC-101 continues to be well tolerated. There were no DLTs up to the 30 milligram per kilogram dose level tested.

現在轉到幻燈片 24 上的數據摘要和後續步驟。這是一項 1b 期試驗，它已經並將繼續招募大部分已經用盡標準護理的患者。在本次數據更新中，ATRC-101 仍然具有良好的耐受性。所測試的劑量水平沒有達到每公斤 30 毫克的 DLT。

What we are learning with this data update is that longer progression-free survival appears to be associated with the ATRC-101 target expression in patients with cancer. While durable disease control was seen across several tumor types, it is too early to quantify and properly qualify the nature of these responses. To do so, we will need to enroll additional patients across cancer types, and our current recruitment efforts will need to focus on underrepresented patients.

我們從本次數據更新中了解到，較長的無進展生存期似乎與癌症患者 ATRC-101 靶標表達相關。雖然在幾種腫瘤類型中看到了持久的疾病控制，但現在量化和正確限定這些反應的性質還為時過早。為此，我們需要招募更多跨癌症類型的患者，而我們目前的招募工作需要重點關注代表性不足的患者。

We continue to focus enrollment based on target expression at the 30-milligram-per-kilogram dose in both the monotherapy and combination with pembrolizumab cohort. In the past several months, we opened the study at five new sites and closed two, and we have contracted with nine additional sites in start-up activities. In addition, we have seven sites undergoing feasibility.

我們繼續根據單藥治療和與派姆單抗聯合治療中 30 毫克每公斤劑量的靶標表達來重點關注入組。在過去的幾個月裡，我們在五個新地點開展了這項研究，並關閉了兩個地點，並且我們還與另外九個地點簽訂了啟動活動合同。此外，我們還有七個地點正在進行可行性研究。

Going forward, a total of 28 centers are expected to participate and contribute to this -- to the study. In addition, we adapted the protocol eligibility criteria based from investigative feedback, and in some instances, work with specific clinical centers to overcome staffing issues post-pandemic. All these activities have already and are expected to continue to help increase enrollment of the study.

展望未來，預計共有 28 個中心將參與這項研究並為此做出貢獻。此外，我們根據調查反饋調整了方案資格標準，並在某些情況下與特定臨床中心合作，以克服大流行後的人員配備問題。所有這些活動已經並且預計將繼續幫助增加該研究的入學人數。

Overall, we are targeting 30 to 40 new additional patients for recruitment distributed across indications to make adequate go/no-go decisions by year-end 2023. That said, because we are enriching for target expression, we have seen not unexpectedly screen failures due to restricting enrollment of patients whose tumor are target positive. The screen failures are in line with prior expectations to target prevalence.

總體而言，我們的目標是招募 30 至 40 名新的患者，這些患者分佈在不同的適應症中，以便在 2023 年底之前做出適當的繼續/不繼續決定。也就是說，由於我們正在豐富目標表達，因此我們不會意外地看到由於篩選失敗限制腫瘤靶點呈陽性的患者的入組。篩查失敗符合之前對目標患病率的預期。

Finally, our recruiting efforts have already seen improvements. The additional data we expect to collect should position us well to enable a go/no-go decision for further development of ATRC-101 by year end, paving the way for determining a registration path with defined commercial opportunity for ATRC-101.

最後，我們的招聘工作已經有所改善。我們期望收集的額外數據將使我們能夠在年底前做出是否進一步開發 ATRC-101 的決定，為確定 ATRC-101 的註冊路徑和明確的商業機會鋪平道路。

I will now turn it over to Stephen to discuss our preclinical pipeline programs.

我現在將把它交給斯蒂芬討論我們的臨床前管道計劃。

Thank you, Philippe. I'll now review three of our late lead oncology programs moving toward candidate nominations. The first highlighted on slide 26 is a novel tumor-specific, anti-glycan antibody that we're advancing as an antibody drug conjugate or ADC, referred subsequently to as antibody 444. 444 is one of a growing number of anti-glycan antibodies that we are uncovering with our platform. This is exciting as aberrant glycosylation has long been recognized as a hallmark of cancer, but this class of targets has been difficult to address through standard methods.

謝謝你，菲利普。現在，我將回顧我們三個已進入候選提名階段的領先腫瘤學項目。第 26 張幻燈片中突出顯示的第一個是一種新型腫瘤特異性抗聚醣抗體，我們正在將其作為抗體藥物偶聯物或 ADC 進行開發，隨後稱為抗體 444。444 是越來越多的抗聚醣抗體之一，我們正在通過我們的平台來揭秘。這是令人興奮的，因為異常糖基化長期以來一直被認為是癌症的標誌，但此類目標很難通過標準方法解決。

As I'll show you, 444 displays uniform and selective binding on tumors with high prevalence on colorectal cancer and is active as an ADC, both in vitro and in vivo. We're currently optimizing both the antibody portion of the molecule and the linker drug portion to yield a candidate -- clinical candidate that we expect to nominate by year end with an IND targeted for late 2024.

正如我將向您展示的，444 對結直腸癌發病率較高的腫瘤表現出均勻和選擇性的結合，並且在體外和體內均作為 ADC 具有活性。我們目前正在優化該分子的抗體部分和連接藥物部分，以產生候選藥物——我們預計將在年底前提名臨床候選藥物，並預計在 2024 年末進行 IND。

The bar plot in the top left of slide 27 shows why we're so excited about this antibody. 444 exhibits strong immunology activity, i.e. two plus and three plus staining in greater than 70% of colorectal cancer. And I hope you can appreciate that the staining is very uniform, in the images to the right, where essentially all tumor cells are positive for the epitope.

第 27 張幻燈片左上角的條形圖顯示了為什麼我們對這種抗體如此興奮。 444表現出很強的免疫學活性，即在大於70%的結直腸癌中進行二加和三加染色。我希望您能意識到右側圖像中的染色非常均勻，基本上所有腫瘤細胞的表位均呈陽性。

We also see high prevalence in gastric cancer and lower prevalence in several indications, including uterine pancreatic, esophageal, and lung cancer. Importantly, we did not detect membranous immunoreactivity on 27 normal fresh frozen tissues. The highest signal in normal tissue is moderate cytoplasmic staining in the stomach, which we suspect from data that I'll share in the coming slides, is not accessible to the antibody.

我們還發現胃癌的患病率很高，而一些適應症的患病率較低，包括子宮胰腺癌、食道癌和肺癌。重要的是，我們沒有在 27 個正常新鮮冷凍組織上檢測到膜免疫反應性。正常組織中的最高信號是胃中的中度細胞質染色，從我將在接下來的幻燈片中分享的數據中我們懷疑抗體無法獲得這種染色。

On slide 28, you can see that consistent with the abundant immunoreactivity in colorectal and gastric cancer, 444 binds to cell lines derived from these tissues highlighted in blue and not to those derived from other tissues. We screen for ADC activity shown on the right. 444 leads to cytotoxicity and cells that express high and low to moderate levels of target in the case of LoVo and NUGC4, respectively.

在幻燈片 28 上，您可以看到，與結直腸癌和胃癌中豐富的免疫反應性一致，444 與源自這些以藍色突出顯示的組織的細胞系結合，而不與源自其他組織的細胞系結合。我們篩選右側顯示的 ADC 活動。在 LoVo 和 NUGC4 的情況下，444 會導致細胞毒性，並且細胞分別表達高水平和低至中等水平的靶標。

On slide 29, you can see that 444 before any affinity maturation. When formatted as an ADC using ZymeLink Auristatin-based linker payload, it leads to dose responsive antitumor activity after a single dose in a LoVo xenograft model. This model expresses a relatively high level of target. But as shown to the right, the level of staining is comparable to what can be found in human cancer, and therefore, is a relevant model system. Importantly, 444 has been tolerated in both single and multiple dose studies in mice without body weight loss or histopathologic findings.

在幻燈片 29 上，您可以看到在任何親和力成熟之前的 444。當使用基於 ZymeLink Auristatin 的接頭有效負載格式化為 ADC 時，它會在 LoVo 異種移植模型中單劑量後產生劑量響應性抗腫瘤活性。該模型表達了較高水平的目標。但如右圖所示，染色水平與人類癌症中的染色水平相當，因此是一個相關的模型系統。重要的是，在小鼠的單劑量和多劑量研究中，444 已被耐受，沒有體重減輕或組織病理學發現。

444 as an ADC has also been explored in initial PK tolerability assessment in rats and has been well tolerated up to 30 mgs per kg with the ZymeLink Auristatin linker payload. I should note that the moderate cytoplasmic staining I pointed out earlier in the human stomach is also observed in both mice and rats. The fact that the ADC is well tolerated in both species suggests again that this intracellular pool of target is not accessible to the ADC.

444 作為 ADC 也在大鼠的初始 PK 耐受性評估中進行了探索，並且通過 ZymeLink Auristatin 連接器有效負載達到了 30 mg/kg 的良好耐受性。我應該指出，我之前指出的人胃中的中等細胞質染色在小鼠和大鼠中也觀察到。 ADC 在兩個物種中均具有良好耐受性的事實再次表明 ADC 無法訪問該細胞內靶標池。

Moving now to slide 30. At this point in the project, we had a very interesting antibody with tumor-specific expression and intriguing antitumor activity but we didn't know the target. Attempts to deorphanize the antibody using standard approaches such as commercial protein or glycan arrays had failed to this point. And as Tito mentioned, we have now enabled whole genome CRISPR screens in-house and 444 was one of the first antibodies we assayed with this approach.

現在轉到幻燈片 30。在項目的這一點上，我們有一種非常有趣的抗體，具有腫瘤特異性表達和有趣的抗腫瘤活性，但我們不知道目標。使用標準方法（例如商業蛋白質或聚醣陣列）對抗體進行去孤兒化的嘗試目前已失敗。正如 Tito 提到的，我們現在已經在內部啟用了全基因組 CRISPR 篩選，444 是我們用這種方法檢測的首批抗體之一。

Using a CRISPR knockout approach, we knocked out genes individually and assess which genes are essential for 444 binding to a flow positive cell line. Three genes were identified as being required for 444 binding: two glycosyltransferases, B4GALNT3 and FUT4, as well as a fucose transporter. A fucose transporter makes sense in the context of FUT4, which requires fewer doses and substrates.

使用 CRISPR 敲除方法，我們單獨敲除基因，並評估哪些基因對於 444 與流式細胞陽性細胞系的結合至關重要。鑑定出 444 結合所需的三個基因：兩種糖基轉移酶 B4GALNT3 和 FUT4，以及岩藻糖轉運蛋白。岩藻糖轉運蛋白在 FUT4 的背景下很有意義，它需要更少的劑量和底物。

Interestingly, when one looks at the expression of the two glycosyltransferases at the RNA level in normal tissue, they're largely not co-expressed, a feature that helps explain the near absence of immunoreactivity in normal tissue. We validated that these two enzymes were required by expressing them in a cell line that did not express the target for 444. Upon co-expression, a dramatic right shift in this flow cytometry plot shown to the right suggests that these enzymes are required to present the glycan on the cell surface, at least in this context. Based on the substrate specificity of these two enzymes, we understand what glycan structure is likely required for binding and are confirming this through biochemical means.

有趣的是，當人們在正常組織中觀察兩種糖基轉移酶在 RNA 水平上的表達時，發現它們基本上不共表達，這一特徵有助於解釋正常組織中幾乎不存在免疫反應性。我們通過在不表達 444 靶標的細胞系中表達這兩種酶來驗證這兩種酶是必需的。共表達後，右側顯示的流式細胞術圖中的顯著右移表明這些酶需要呈現細胞表面上的聚醣，至少在這種情況下。根據這兩種酶的底物特異性，我們了解結合可能需要什麼聚醣結構，並通過生化手段證實這一點。

Advancing to slide 31, I alluded to the fact that 444 is one of a growing number of anti-glycan antibodies being discovered by our platform. In fact, half of the antibodies for which we have identified the target are anti-glycan antibody. Our platform appears uniquely positioned to help uncover the potential of this underexploited class of antibodies.

前進到幻燈片 31，我提到了這樣一個事實：444 是我們平台發現的越來越多的抗聚醣抗體之一。事實上，我們已確定目標的抗體中有一半是抗聚醣抗體。我們的平台具有獨特的定位，可以幫助發現此類未充分利用的抗體的潛力。

The platform, of course, also identifies the antibodies to protein targets. And one theme that has emerged is the mislocalization of normal intracellular targets to the cell surface. A good example of this is our next late lead asset, 958, highlighted on slide 32.

當然，該平台還可以識別蛋白質靶標的抗體。出現的一個主題是正常細胞內靶點錯誤定位到細胞表面。一個很好的例子是我們的下一個後期主導資產 958，在幻燈片 32 中突出顯示。

958 recognizes an RNA-binding protein that is normally sequestered in the nucleus, but is mislocalized to the cell surface in tumors potentially be a stress granule. 958 is advancing as a CD3 bispecific T cell engager in collaboration with Xencor where Atreca is taking the lead on the preclinical and clinical development. We expect to nominate a clinical candidate by year end and are targeting an IND submission by early 2025.

958 識別一種 RNA 結合蛋白，該蛋白通常隔離在細胞核中，但在腫瘤中錯誤定位到細胞表面，可能是一種應激顆粒。 958 正在與 Xencor 合作，發展成為 CD3 雙特異性 T 細胞參與劑，其中 Atreca 在臨床前和臨床開發方面處於領先地位。我們預計在年底前提名一名臨床候選人，併計劃在 2025 年初提交 IND 申請。

On Slide 33, similar to the anti-glycan antibody, 444, the native antibody from -- of 958 straight from the patient shows preclinical activity. In this case, however, we formatted the antibody as a T cell engager using Xencor's XmAb CD3 bispecific platform.

在幻燈片 33 上，與抗聚醣抗體 444 類似，直接來自患者的 958 種天然抗體顯示出臨床前活性。然而，在這種情況下，我們使用 Xencor 的 XmAb CD3 雙特異性平台將抗體格式化為 T 細胞接合劑。

As shown on the left, the 958 bispecific leads to tumor stasis in a target positive prostate cancer xenograft model in the blue line. We're currently optimizing the antibody to further enhance the potency to match or beat the positive control T cell bispecific use in this study, which is directed against a well-known prostate cancer target PSMA shown in orange.

如左圖所示，958 雙特異性導致藍線靶標陽性前列腺癌異種移植模型中的腫瘤停滯。我們目前正在優化該抗體，以進一步增強其效力，以匹配或擊敗本研究中使用的陽性對照 T 細胞雙特異性抗體，該抗體針對眾所周知的前列腺癌靶標 PSMA（以橙色顯示）。

On the right, you can see that 958 leads to the expected pharmacodynamic effects for molecules with this mechanism of action, including robust immune activation as evidenced by an increase in interferon gamma levels in plasma and expansion of CD8-positive T cells in blood. 958 is the first molecule to advance as part of our collaboration with Xencor, the details of which are described in more detail on slide 34.

在右側，您可以看到 958 為具有這種作用機制的分子帶來了預期的藥效效應，包括血漿中乾擾素 γ 水平的增加和血液中 CD8 陽性 T 細胞的擴增所證明的強大的免疫激活。 958 是我們與 Xencor 合作的第一個進展分子，其細節在幻燈片 34 中有更詳細的描述。

In this collaboration, Atreca will provide antibodies against novel targets, and Xencor will engineer bispecific antibodies using their XmAb CD3 platform. The two companies will mutually select up to two joint programs for further development and commercialization, with each partner sharing 50% of the costs and profit. While each company will lead one of the joint programs, the agreement allows each partner to pursue up to two programs independently.

在此次合作中，Atreca 將提供針對新靶標的抗體，Xencor 將使用其 XmAb CD3 平台設計雙特異性抗體。兩家公司將共同選擇最多兩個聯合項目進行進一步開發和商業化，每個合作夥伴分擔50%的成本和利潤。雖然每家公司將領導一項聯合項目，但該協議允許每個合作夥伴獨立開展最多兩個項目。

The last oncology lead I will review is highlighted on slide 35. 597 is our anti-EphA2 antibody, which targets a novel, well-conserved membrane proximal epitope on EphA2, a validated oncology target that is overexpressed in a range of tumor types. We have generated a series of antibody variants with a range of affinities to EphA2 and have tested these in various weaponization schemes where they're broadly active. Previously, we advanced the high-affinity variant as an ADC and are now evaluating antibody variants in CD3 T cell engager format based on the in vivo activity we've observed.

我要回顧的最後一個腫瘤學線索在幻燈片 35 中突出顯示。597 是我們的抗 EphA2 抗體，它針對 EphA2 上一個新穎的、保守的膜近端表位，EphA2 是一個經過驗證的腫瘤學靶點，在一系列腫瘤類型中過度表達。我們已經生成了一系列與 EphA2 具有一定親和力的抗體變體，並在廣泛活躍的各種武器化方案中測試了這些抗體變體。此前，我們將高親和力變體作為 ADC 進行了改進，現在正在根據我們觀察到的體內活性評估 CD3 T 細胞接合器形式的抗體變體。

Moving to slide 36. I hope you share our excitement about the molecules I highlighted for you today. We're equally excited about molecules coming from the platform, which are at an earlier stage. As Tito mentioned at the beginning of the presentation, we believe investments we've made across our platform, especially around target identification with the implementation of CRISPR screening, have eliminated common bottlenecks and made the platform even more productive. We believe Atreca is well positioned to capitalize on the discovery and development of novel oncology targets.

轉到幻燈片 36。我希望您能分享我們對我今天為您強調的分子的興奮。我們對來自該平台的分子同樣感到興奮，這些分子還處於早期階段。正如 Tito 在演講開始時提到的那樣，我們相信我們在整個平台上所做的投資，特別是在實施 CRISPR 篩選的目標識別方面，已經消除了常見的瓶頸，並使平台更加高效。我們相信 Atreca 處於有利地位，可以利用新腫瘤學靶點的發現和開發。

Finally, while not an internal pipeline molecule, we wish to highlight another exciting asset, Atreca's anti-malaria antibody, ATRC-501, on slide 37. ATRC-501 is an engineered version of an Atreca-discovered antibody designed to prevent malaria infection. The antibody is licensed to the Gates Medical Research Institute, which is preparing to file an IND this year. Atreca retains rights in the US, Europe, and parts of Asia with potential product development of opportunities, including prophylaxis for those traveling to malaria endemic regions.

最後，雖然不是內部管道分子，但我們希望在幻燈片 37 上強調另一個令人興奮的資產，Atreca 的抗瘧疾抗體 ATRC-501。ATRC-501 是 Atreca 發現的抗體的工程版本，旨在預防瘧疾感染。該抗體已獲得蓋茨醫學研究所的許可，該研究所正準備於今年提交 IND 申請。 Atreca 保留在美國、歐洲和亞洲部分地區的權利，擁有潛在的產品開發機會，包括為前往瘧疾流行地區的人們提供預防措施。

And with that, I'll hand it back over to John to discuss our upcoming milestones and provide an overview of our financials and IP.

接下來，我將把它交還給約翰，討論我們即將到來的里程碑，並概述我們的財務和知識產權。

Thank you, Steven. So slide 39 is an overview of our upcoming milestones. As Philippe noted, we are planning to provide updated data and a go/no-go decision for Phase 2 development of ATRC-101 later this year and potentially begin Phase 2 studies next year.

謝謝你，史蒂文。幻燈片 39 概述了我們即將到來的里程碑。正如 Philippe 指出的那樣，我們計劃在今年晚些時候為 ATRC-101 的第二階段開發提供更新的數據和進行/不進行的決定，並可能在明年開始第二階段研究。

On the preclinical side, we expect to nominate clinical candidates in the 444 and 958 programs later this year and are targeting INDs in late 2024 and early 2025, respectively. And behind those, our early stage discovery and lead generation efforts are ongoing. Finally, Gates MRI continues to advance the ATRC-501 and is expecting to file an IND this year.

在臨床前方面，我們預計將在今年晚些時候在 444 和 958 項目中提名臨床候選人，並分別在 2024 年底和 2025 年初確定 IND。在這些背後，我們的早期發現和潛在客戶開發工作正在進行中。最後，Gates MRI 繼續推進 ATRC-501，預計今年提交 IND。

Turning to slide 40, this addresses our financials and intellectual property. As of December 31 of last year, we had $70.5 million in cash equivalents and investments which is expected to fund operations through the end of this year. We have a strong IP position and patents issued covering critical aspects of Atreca discovery platform as well as ATRC-101 and related antibodies, with pending applications covering other pipeline assets.

轉向幻燈片 40，這涉及我們的財務和知識產權問題。截至去年 12 月 31 日，我們擁有 7050 萬美元的現金等價物和投資，預計將為今年年底的運營提供資金。我們擁有強大的知識產權地位和已頒發的專利，涵蓋 Atreca 發現平台以及 ATRC-101 和相關抗體的關鍵方面，還有涵蓋其他管道資產的待決申請。

That concludes today's prepared remarks. We'd like to thank our trial participants and their families as well as investigators and research staff at our clinical sites. Thanks, again, to everyone who joined the conference call and webcast today.

今天準備好的發言到此結束。我們要感謝我們的試驗參與者及其家人以及我們臨床中心的調查人員和研究人員。再次感謝今天參加電話會議和網絡廣播的所有人。

With that, operator, could you please open the line for Q&A?

那麼，接線員，您可以開通問答線路嗎？

(Operator Instructions)

（操作員說明）

Divya Rao, Cohen.

迪維亞·拉奧，科恩。

Hi, guys. Thanks for taking our question today. For Phil, just based on your experience, when you're trying to enrich for high H-score patients, what would you say is the percent of patients that fit that eligibility criteria? And then I guess as a follow-up, how does that change in terms of indications that maybe you're not seeing as many patients enrolled in?

嗨，大家好。感謝您今天提出我們的問題。對於 Phil 來說，僅根據您的經驗，當您嘗試豐富高 H 分數患者時，您認為符合該資格標準的患者百分比是多少？然後我想作為後續行動，在可能沒有看到那麼多患者入組的跡象方面，情況會發生怎樣的變化？

Philippe?

菲利普？

Yes. Thank you. So as you know, in the preclinical assessments of the program, we had done some prevalence assessments in microarrays. So these are tumors in microarrays, looking at the presence of target on these tumors. And we had assessed that somewhere in the neighborhood of between 30% to 50% of the tumors that we were looking across all the indications, we're expressing the target.

是的。謝謝。如您所知，在該計劃的臨床前評估中，我們對微陣列進行了一些患病率評估。這些是微陣列中的腫瘤，觀察這些腫瘤上是否存在靶點。我們評估了在所有適應症中我們所觀察的腫瘤中 30% 到 50% 附近的某個地方，我們正在表達靶標。

What we're observing in the clinical trial is similar to that. It's consistent with that prevalence data that we had generated previously. And depending which indication we're looking for the most part, we're seeing about 50% of the tumors expressing the target.

我們在臨床試驗中觀察到的情況與此類似。這與我們之前生成的流行率數據一致。根據我們主要尋找的適應症，我們發現大約 50% 的腫瘤表達該靶點。

That's helpful. Congrats on all the data.

這很有幫助。恭喜獲得所有數據。

Well, thank you very much.

好的，謝謝。

Roger Song, Jefferies.

羅傑·宋，杰弗里斯。

Great. Thanks for the data update and taking our questions. A couple from us. So the first one is, you know, for this, you enroll the patient, you have median 5 prior lines. Can you just help us to conceptualize what is the expected PFS in this population from standard of care or whatever the care -- whatever the therapy amenable to those patients?

偉大的。感謝您更新數據並回答我們的問題。我們的一對。所以第一個是，你知道，為此，你登記患者，你有中位數 5 條先前線。您能否幫助我們概念化該人群在標準護理或任何護理（無論適合這些患者的治療方法）下的預期 PFS 是多少？

Yes. So, Roger, it depends which indication you're looking at. For some patients, as you may be aware, such as lung cancer, breast cancer will be another example. As you begin to exhaust standard of care, the expected progression-free survival gets shorter and shorter with subsequent lines of therapy.

是的。所以，羅傑，這取決於你正在尋找哪種跡象。您可能知道，對於某些患者，例如肺癌，乳腺癌是另一個例子。當您開始用盡標準護理時，預期的無進展生存期隨著後續治療的進行而變得越來越短。

There are some other indications of where you can observe from time to time indolent disease. I would think come from colorectal cancers or like that. And as you know, with melanoma as well, we have seen with the advent of immunotherapy individuals now having longer periods where you see progression-free survivals occurring.

還有一些其他跡象表明您可以不時觀察到惰性疾病。我認為來自結直腸癌或類似的疾病。如您所知，對於黑色素瘤，隨著免疫療法的出現，我們看到個體現在有更長的無進展生存期。

I think we have -- for the most part in our study with the patients that we are looking at, they come in already heavily pretreated. They tend to have an ECOG performance status of 1, which also predict worse outcome for these individuals. And so for them, I think, looking at the data, I think it's important to note any one that would go past the sixth-month mark. I think the PFS at six months is an important landmark. The PFS at four months for some of those indication may also be equally interesting to look at.

我認為，在我們對我們正在研究的患者進行的研究中，大多數情況下，他們已經接受了嚴格的預處理。他們的 ECOG 表現狀態往往為 1，這也預示著這些人的結果會更差。因此，我認為，對於他們來說，查看數據，重要的是要注意任何超過六個月大關的數據。我認為六個月的 PFS 是一個重要的里程碑。其中一些適應症的四個月 PFS 也同樣值得關注。

Yes, I'd just add to that, Roger, that I think, you know, given the heterogeneity of these patients, different tumor types, in the sort of open-label nature of the trial, I think we certainly need to have more patients before we could really draw conclusions about the efficacy or the activity that we're seeing, how it compares with standard of care.

是的，我想補充一點，羅傑，我認為，考慮到這些患者的異質性、不同的腫瘤類型，在試驗的開放標籤性質中，我認為我們當然需要更多在我們能夠真正得出關於我們所看到的療效或活動的結論之前，以及它與標準護理相比如何。

I think we are encouraged by the fact that where we do see more disease control and where we have seen responses is primarily in the context of patients who are expecting target, so that does give us some encouragement that what we're seeing is really a function of ATRC-101. But clearly, we'll need more patients and that's why we're continuing to enroll, adding additional centers, and hope to have sufficient data by the end of this year really to make a decision about whether and where to go to Phase 2 for ATRC-101.

我認為我們受到以下事實的鼓舞：我們確實看到了更多的疾病控制，並且我們看到的反應主要是在期待目標的患者的背景下，所以這確實給了我們一些鼓勵，我們所看到的確實是一個ATRC-101 的功能。但顯然，我們需要更多的患者，這就是我們繼續招募、增加更多中心的原因，並希望在今年年底之前獲得足夠的數據，以便真正決定是否以及在哪裡進行第二階段治療ATRC-101。

Okay, great. Maybe just -- that leads to my next question regarding the additional patient about 40 to 50 patients. Would you expect that those patients will be slightly different from what you have enrolled in terms of the tumor type and the prior line of therapy?

好的，太好了。也許只是 - 這引出了我的下一個問題，涉及大約 40 到 50 名額外患者。您是否認為這些患者在腫瘤類型和既往治療方案方面與您入組的患者略有不同？

And just remind us, so what is the breakdown between the monotherapy versus the combination therapy? And when you make the go/no-go decision, what will be the key efficacy endpoint you were looking at, like had disease control or our PFS started for the year? Sorry for the long, long question here.

請提醒我們，單一療法與聯合療法之間的區別是什麼？當您做出繼續/不繼續的決定時，您關注的關鍵療效終點是什麼，例如今年是否開始疾病控製或 PFS？很抱歉這裡問了一個很長很長的問題。

So I'll try to address all the questions and the points that you have raised. I think for the patients that are going to be enrolling, the 30 to 40 patients that we expect to enroll that will be new, with the changes that we have made going to centers that are more adept to enrolling the Phase 2 patients as opposed to Phase 1.

因此，我將盡力解決您提出的所有問題和觀點。我認為對於將要入組的患者來說，我們期望入組的 30 到 40 名患者將是新的，我們所做的改變將進入更擅長招募 2 期患者的中心，而不是階段1。

As you know, Phase 1 units are highly specialized. Here, what we have done is got two centers that are hybrid between academic centers and community centers where we are seeing patients, a greater number of patients that would be eligible for our trial. So that's one point to make.

如您所知，第一階段的單位高度專業化。在這裡，我們所做的是建立兩個介於學術中心和社區中心之間的混合中心，我們在那裡接待患者，更多的患者有資格參加我們的試驗。這是需要指出的一點。

And what we expect to see there is a distribution across the various tumor types that we are seeking to enroll into. Some of the centers are more likely to enroll individuals, for example, with lung cancer or those with breast cancer. But we are also looking at centers that can help augment our database for head-and-neck and urothelial cancers as well.

我們期望看到我們正在尋求招募的各種腫瘤類型之間的分佈。一些中心更有可能招收患有肺癌或乳腺癌的患者。但我們也在尋找可以幫助擴大我們的頭頸癌和尿路上皮癌數據庫的中心。

So we're looking. Our recruitment efforts are targeted at this point, and we're looking to try to supplement those underrepresented patient populations. And the goal for that is really to -- for us to be able to look at where our strongest signal comes from. And there, we'll be looking at, I think, response rates, obviously responders.

所以我們正在尋找。我們的招募工作就是針對這一點，我們希望嘗試補充那些代表性不足的患者群體。其目標實際上是讓我們能夠了解最強信號的來源。我認為，我們將在那里關注回复率，顯然是回复者。

As you know, we have the lung cancer and the melanoma patients that has been durable. I think that has been notable. But what is new with the data that we're presenting today is really this notion of disease control and the ability to see patients staying on study for a longer period of time. So we'll be incorporating a component of disease control into our decision algorithm. And we plan to update you at some point about how we're going to approach that and on the basis, of course, from the -- on sound analytic principles.

如您所知，我們有持久的肺癌和黑色素瘤患者。我認為這一點值得注意。但我們今天提供的數據的新內容實際上是疾病控制的概念以及讓患者更長時間地進行研究的能力。因此，我們將把疾病控制的一部分納入我們的決策算法中。我們計劃在某個時候向您通報我們將如何處理這一問題，當然，這是基於合理的分析原則。

So with regards to the type of patients that we're planning to see, the eligibility criteria remains as it is and will continue to remain as is for the time being. So we don't really expect that the patients that we'll be seeing coming on to study will be much different. There will be individuals that have exhausted, for the most part, standard of care and have either advanced or metastatic disease. And so we think that these patients will be similar to the ones that we've enrolled to date.

因此，對於我們計劃看診的患者類型，資格標准保持不變，並將暫時繼續保持不變。因此，我們並不真正期望我們將要看到的接受研究的患者會有很大的不同。有些人在很大程度上已經用盡了標準護理，並且患有晚期或轉移性疾病。因此，我們認為這些患者將與我們迄今為止招募的患者相似。

We're continuing to enrich our target as of today and those patients are getting enrolled at the 30-milligram-per-kilogram dose cohort.

從今天開始，我們將繼續豐富我們的目標，這些患者將被納入每公斤 30 毫克的劑量隊列。

And in terms of I think what we objectively need to see in terms of our response rate or durability of either responses for disease control or generally, I think it depends also on the tumor type, right? As Philippe alluded to, some of these are tumor types where it's not entirely uncommon. We have patients with indolent disease.

就我認為我們客觀需要看到的疾病控製或一般反應的反應率或持久性而言，我認為這也取決於腫瘤類型，對嗎？正如菲利普提到的，其中一些是腫瘤類型，這種情況並不完全罕見。我們有惰性疾病的患者。

And then there are other settings. If we take our, you know, response with the 50% tumor reduction in lung cancer, that's fifth-line lung cancer. That's a setting where we wouldn't expect to see indolent disease. But then we have to overlay on top of that, what's the unmet need? What would be -- what would the regulatory hurdle be? Because the whole point of that randomized Phase 2 trial is really to set up what could be the potential registration. So I think it'll be taking all of those things into consideration and applying relatively high bar, particularly in any setting where there's a well-established standard of care.

然後還有其他設置。如果我們以肺癌腫瘤減少 50% 的反應為例，那就是五線肺癌。在這種情況下，我們不會期望看到惰性疾病。但除此之外，我們還必須考慮未滿足的需求是什麼？監管障礙會是什麼？因為隨機二期試驗的全部目的實際上是確定潛在的註冊。因此，我認為它將考慮所有這些因素並應用相對較高的標準，特別是在任何有完善的護理標準的環境中。

Got it. Yes. Thanks for the thorough answer. Just to clarify, what is the breakdown between the monotherapy and combination therapy for the new 30 to 40 patients enrollment?

知道了。是的。感謝您的徹底回答。需要澄清的是，對於新入組的 30 至 40 名患者，單一療法和聯合療法的具體情況如何？

So this will be obviously consistent with the eligibility criteria. So for patients that would be considered to continue on pembro, to receive the pembro-containing regimen, those indications are, as you know, based on the pembro label. So there, we have both some differences with the monotherapy and the monotherapy, as you know, was based on our earlier data showing that there was a high prevalence of target in these various tumor types.

所以這顯然符合資格標準。因此，對於考慮繼續使用 pembro 並接受含有 pembro 的方案的患者，如您所知，這些適應症是基於 pembro 標籤的。因此，我們與單一療法存在一些差異，正如你所知，單一療法是基於我們早期的數據顯示，在這些不同的腫瘤類型中靶點的患病率很高。

So if the physician thinks that pembro is not indicated or the patient had already received a PD-1 or PD-L1 agents and unlikely to respond, it is likely that they'll be brought on to the monotherapy if they meet eligibility. And for those for whom the physician believes that continuing on pembro would be suitable, we would probably see those coming on to the combination.

因此，如果醫生認為 pembro 沒有適應症，或者患者已經接受了 PD-1 或​​ PD-L1 藥物且不太可能有反應，那麼如果他們符合資格，很可能會接受單一療法。對於那些醫生認為繼續服用 pembro 合適的人來說，我們可能會看到那些人開始接受聯合用藥。

And I should point out that urothelial malignancies, esophageal malignancies, and head-and-neck malignancies, and a subset of breast cancer, the triple-negative breast cancers and the hepatocellular carcinoma would be indications that we would see in the combination arm that would not be appropriate for the monotherapy arm based on eligibility criteria.

我應該指出，尿路上皮惡性腫瘤、食管惡性腫瘤、頭頸惡性腫瘤以及乳腺癌的一個子集、三陰性乳腺癌和肝細胞癌將是我們在聯合治療組中看到的跡象根據資格標準，不適合單一治療組。

Yes. And I think even in the setting where we have cohorts open for monotherapy and combo with pembrolizumab, I think we would likely need to show more suggestion of single-agent activity for the FDA anyway. So to some extent, we'd like to see more combination patients.

是的。我認為，即使在我們有隊列開放單一療法和與派姆單抗聯合治療的情況下，我認為我們可能需要向 FDA 提供更多關於單藥活性的建議。所以在某種程度上，我們希望看到更多的聯合患者。

But to some extent, we also benefit from more monotherapy because I think that's something that -- that individual contribution is something that probably the FDA would want us to be after. But at this point, those centers, most of them would have been basically the choice and use their own discretion, at least, ovarian, colorectal.

但在某種程度上，我們也受益於更多的單一療法，因為我認為個人貢獻可能是 FDA 希望我們追求的東西。但在這一點上，那些中心，大部分基本上都是自己選擇和運用的，至少是卵巢、結直腸。

Got you. Yes, that makes sense. Okay. Thank you.

明白你了。是的，這是有道理的。好的。謝謝。

Thank you, Roger.

謝謝你，羅傑。

John Newman, Canaccord.

約翰·紐曼，Canaccord。

Hey, thanks for taking my question. Just wondering with the currently ongoing Phase 1 study for 101, how much follow-up time will be allotted? Just wondering if you'll be able to follow the study longer term for things like overall survival, where perhaps there's a signal that shows up that doesn't initially show up in the response rate. Thanks.

嘿，謝謝你回答我的問題。只是想知道目前正在進行的 101 第一階段研究，將分配多少後續時間？只是想知道您是否能夠長期跟踪這項研究，了解諸如總體生存率之類的問題，其中可能會出現一個最初沒有出現在響應率中的信號。謝謝。

Yes. So right now, the data that's been collected obviously is done response rates. And we're looking at progression-free intervals. Survival is collected when that event occurs for patients that are on study during the period of follow-up, but we are not following patients once they come off study. So the overall survival data would not be something that we would expect to report on this trial. I think what we're looking at is for response rate and disease control to give us an idea of the signal and help us prioritize which indication is most likely to be seeing -- driving some kind of benefit from being treated with ATRC-101.

是的。因此，現在收集的數據顯然是完成響應率。我們正在研究無進展間隔。在隨訪期間接受研究的患者發生該事件時收集生存率，但一旦患者結束研究，我們就不會對其進行跟踪。因此，我們不會期望在該試驗中報告總體生存數據。我認為我們正在關注的是反應率和疾病控制，以便讓我們了解信號並幫助我們優先考慮最有可能看到的適應症——從 ATRC-101 治療中獲得某種益處。

And that sets the stage really for the Phase 2 study that John was talking about where they are, in a more formal way, and ideally, in a controlled fashion with appropriate control, we would be assessing about what a true treatment effect would be for Phase 3 and in order to appropriately design the Phase 3 trial. And that Phase 2 could include collecting survival data.

這確實為約翰正在談論的第二階段研究奠定了基礎，以更正式的方式，理想情況下，以適當控制的受控方式，我們將評估真正的治療效果是什麼第 3 階段，以便適當設計第 3 階段試驗。第二階段可能包括收集生存數據。

Okay, great. Thanks.

好的，太好了。謝謝。

Thanks, John.

謝謝，約翰。

Tony Butler, EF Hutton.

托尼·巴特勒，EF·赫頓。

Yes, thanks very much. So if I understand correctly, preclinical work had demonstrated that ATRC-101 actually remodeled the tumor microenvironment, if I'm correct in that.

是的，非常感謝。因此，如果我理解正確的話，臨床前工作已經證明 ATRC-101 實際上重塑了腫瘤微環境（如果我的觀點是正確的）。

If that's true, one of the questions that comes to mind is this notion of combination where, as I think you stated, utilizing pembro with 101 was really related to those indications where pembro was already indicated. If that's true, that's fine. I'm respectful of that.

如果這是真的，我想到的問題之一就是這種組合的概念，正如我認為您所說的，使用 pembro 與 101 確實與 pembro 已經指示的那些指示相關。如果這是真的，那很好。我對此表示尊重。

But the real question is in cold tumors, for example, in CRC and/or ovarian where pembro just has no effect. there may be -- if in fact you do get TME remodeling, there may be some really decent signals here where in those tumors, that combination could then therefore be advantageous.

但真正的問題是在冷腫瘤中，例如，在結直腸癌和/或卵巢中，pembro 沒有任何作用。如果事實上你確實進行了 TME 重塑，那麼在這些腫瘤中可能會出現一些非常好的信號，因此這種組合可能是有利的。

And so for example, it wouldn't take a lot from a response rate to really demonstrate in the late-line CRC patient that you really have something of benefit. I am respectful that in monotherapy, you may have modest benefit. But yet certainly in combination, there's at least a question here that if you could show anything better than regorafenib, you really have an opportunity set. And I'm just throwing this out as a thought, if it's the directionally correct, or maybe what you think about it. Thanks.

例如，不需要太多的反應率就能真正向晚期 CRC 患者證明您確實有一些好處。我很尊重，在單一療法中，您可能會獲得一定的益處。但總的來說，至少有一個問題是，如果你能展示出比瑞戈非尼更好的東西，那麼你確實有一個機會。我只是將其作為一個想法拋出，如果它的方向是正確的，或者也許你對此有何看法。謝謝。

Tito, maybe you want to address that from the preclinical side and then, I don't know, maybe have some further thoughts. Thanks for the question, Tony.

蒂托，也許你想從臨床前方面解決這個問題，然後，我不知道，也許有一些進一步的想法。謝謝你的提問，托尼。

Yes, Tony, so you are right. In the sense that if the mechanism is directed towards the innate immune system, then that upstream of agents to act on T cells like anti-PD-1 or PD-L1 checkpoint inhibitors. And so yes, in principle, that converting tumors that normally don't have much of an immune response with ATRC-101 is possible. And we all know that as you point out, CRC is one of those tumor types.

是的，托尼，所以你是對的。從某種意義上說，如果該機製針對先天免疫系統，那麼就是作用於 T 細胞的藥物的上游，如抗 PD-1 或​​ PD-L1 檢查點抑製劑。因此，原則上來說，ATRC-101 可以轉化通常沒有太多免疫反應的腫瘤。我們都知道，正如您所指出的，結直腸癌是其中一種腫瘤類型。

Yes. From a clinical -- and you raised, I think, a very provocative thought and question that I think would be at some point worth addressing in the clinical setting. I think the -- as you know, the individuals with mismatch repair or MSI high colon cancer are more likely to have a response with pembrolizumab of PD-1 or PD-L1 agents.

是的。我認為，您從臨床角度提出了一個非常具有挑戰性的想法和問題，我認為在某些時候值得在臨床環境中解決。我認為，如您所知，具有錯配修復或 MSI 高結腸癌的個體更有可能對 PD-1 或​​ PD-L1 藥物的派姆單抗產生反應。

And I think this concept of cold and converting a cold tumor to something that is more likely to respond is something that is worth investigating for sure.

我認為這種冷和將冷腫瘤轉化為更有可能產生反應的概念確實值得研究。

Thanks very much.

非常感謝。

Good suggestion, Tony. Thank you for raising it.

好建議，托尼。謝謝你提出來。

Stephen Willey, Stifel.

斯蒂芬·威利，斯蒂菲爾。

Yeah. Good afternoon, guys. Thanks for taking my question. I think I've asked you this before, but I'm going to ask it again. And just curious if in this incremental patient data set you were able to somehow look at longitudinal H-score expression just as a way to assess the stability of target expression over time.

是的。下午好，伙計們。感謝您提出我的問題。我想我以前已經問過你這個問題了，但我想再問一次。只是好奇，在這個增量患者數據集中，您是否能夠以某種方式查看縱向 H 分數表達，作為評估目標表達隨時間變化的穩定性的一種方法。

So thank you for the question. We are collecting biopsies well on studies for patients that consent to it. And we are planning to do some analysis longitudinally for those matched biopsies that we've obtained. As you know, these are -- they are studies are not that easy to conduct. And with small numbers, we have to be careful with entrances.

謝謝你的提問。我們正在為同意的患者收集活檢樣本以進行研究。我們計劃對我們獲得的那些匹配的活檢進行一些縱向分析。如您所知，這些研究並不容易進行。由於人數較少，我們必須小心入口。

To date, what we have is the baseline data. We batched the assessments and plan to analyze this at the final analysis. So we have not looked at the serial biopsies yet for those -- for the patients who have given us permission to go ahead and sample again.

到目前為止，我們擁有的是基線數據。我們對評估進行了批量處理，併計劃在最終分析時對此進行分析。因此，我們還沒有對那些允許我們繼續進行再次採樣的患者進行連續活檢。

And just for clarity, we do it during -- at baseline, we do it during the first cycle and we do it also, like the disease progression.

為了清楚起見，我們在基線期間這樣做，我們在第一個週期期間這樣做，我們也這樣做，就像疾病進展一樣。

Okay. And then I think eligibility for the combo cohort required either progression on a PD-1 or L1 targeting mAb and/or stable disease on a PD-1 or L1 targeting mAb. I'm just curious if you know offhand if the incremental patients enrolled into the combo cohort either fit the progression definition or if there were some patients in there who also fit the stable disease definition.

好的。然後我認為組合隊列的資格需要 PD-1 或​​ L1 靶向 mAb 取得進展和/或 PD-1 或​​ L1 靶向 mAb 疾病穩定。我只是好奇你是否立即知道加入組合隊列的增量患者是否符合進展定義，或者其中是否有一些患者也符合穩定疾病定義。

Yes. So I think the eligibility criteria is worded slightly differently. It's an unsatisfactory response while on the PD-1 or PD-L1 agent and/or disease progression. So there, in the opinion of the physician, the response that was obtained while on the PD-1 or PD-L1 would have to be unsatisfactory and require the institution of new therapy.

是的。所以我認為資格標準的措辭略有不同。在使用 PD-1 或​​ PD-L1 藥物和/或疾病進展時，這是一種不令人滿意的反應。因此，在醫生看來，使用 PD-1 或​​ PD-L1 時獲得的反應一定不能令人滿意，需要製定新的療法。

What we have is, for the most part, looking at those nine individuals, the reason for the last therapy was really a lack of efficacy and progressive disease. So looking at those individuals, I would say that most of them would have had progressive disease.

我們所掌握的是，在很大程度上，觀察這九個人，最後一次治療的原因實際上是缺乏療效和疾病進展。因此，看看這些人，我想說他們中的大多數人都患有進行性疾病。

Okay. And just with respect to the goal of enrolling an additional 30 to 40 patients before the end of this year, I know you've kind of talked about some of the headwinds that a lot of these Phase 1 sites are facing, and we've heard that from other companies as well.

好的。就在今年年底前招募 30 至 40 名患者的目標而言，我知道您已經談到了許多第一階段站點面臨的一些不利因素，我們已經也從其他公司聽說過。

But I guess, would you still -- is the 30 to 40 incremental amount of patient data, is that requisite for making a no-go decision before year end, or is that something that is a little bit fungible in terms of timelines?

但我想，您仍然會 - 30 到 40 份增量的患者數據是在年底前做出不做決定的必要條件嗎？還是說這在時間安排上有點可替代？

Well, we -- so as you know, the trial is currently set up as a final two-stage study and with criteria for expansion within specific indication. I think like early Phase 1 studies as you learn about your drug and you begin to collect information, adapting your approach and incorporating what you're learning along the way is something that is done by most companies and certainly encouraged even by health authorities.

嗯，正如你所知，該試驗目前被設置為最終的兩階段研究，並具有在特定適應症範圍內擴展的標準。我認為，就像早期的第一階段研究一樣，當你了解你的藥物並開始收集信息時，調整你的方法並結合你一路上學到的東西是大多數公司所做的事情，甚至受到衛生當局的鼓勵。

So early in trial development, we tend to busy as well. We tend to adapt as we learn more about our drug, either on the safety side or on the activity side or even sometimes with pharmacokinetics. We can certainly modify the way we approach looking at these data.

所以在試驗開發的早期，我們也往往很忙。當我們對藥物了解更多時，無論是在安全性方面還是在活性方面，甚至有時在藥代動力學方面，我們傾向於適應。我們當然可以改變查看這些數據的方式。

What is new with today's presentation is the notion of disease control or stabilization of disease or durability of response. And I think that's a very important new information that we have today. If we think about a higher bar for making decisions, I think applying a bar that not only looks at response rate, but also looks at some form of disease control would allow us to prioritize indications moving forward.

今天的演講的新內容是疾病控製或疾病穩定或反應持久性的概念。我認為這是我們今天獲得的非常重要的新信息。如果我們考慮制定更高的決策標準，我認為應用一個不僅考慮響應率而且考慮某種形式的疾病控制的標準將使我們能夠優先考慮前進的適應症。

And for that, I don't think we would need to expand each one of those indications as we had planned earlier. And we can probably make those decisions based on sound analytics principles using data and statistics with fewer patients in each one of the categories.

為此，我認為我們不需要像我們之前計劃的那樣擴大每一項適應症。我們或許可以根據合理的分析原則，使用每一類別中較少的患者的數據和統計數據來做出這些決定。

Okay. And then maybe just lastly, just in terms of -- I thought it was interesting that you disclosed that about half of the antibodies that you're disclosing are actually against these glycan targets, which I know from -- as you mentioned, kind of the conventional immunization perspective have been really hard. These are carbohydrates.

好的。然後也許最後，就 - 我認為有趣的是，你披露了你所披露的大約一半的抗體實際上是針對這些聚醣目標的，我從中了解到 - 正如你所提到的，有點傳統的免疫觀點確實很難。這些是碳水化合物。

Just curious as to kind of where you think your progress puts you from a collaborative position, just kind of given the amount of interest there has been around this target class historically?

只是好奇，考慮到歷史上人們對這個目標類別的興趣，你認為你的進步會讓你脫離協作的位置嗎？

Hi, Stephen, so I'll take that one. So we've -- we're in a number of discussions about programs, obviously. The profile of 444, as Stephen described it, is proving to be quite attractive and garnering a great deal of interest. You have something that's binding a target expressed at certainly high levels than the majority of colorectal cancer patients where there's huge unmet need. And yet you see great potency and lack of the safety signals so far, even with an Fv that has not yet been optimized.

嗨，史蒂芬，我就拿那個吧。顯然，我們正在進行許多有關項目的討論。正如斯蒂芬所描述的那樣，444 的個人資料被證明非常有吸引力並引起了極大的興趣。你有一些東西可以結合一個靶標，其表達水平肯定比大多數結直腸癌患者高，而這些患者的需求有巨大的未滿足。然而，到目前為止，即使 Fv 尚未優化，您仍會看到巨大的效力，但缺乏安全信號。

And so yes, I think you're right. There are a couple of anti-glycan antibodies that have reached commercial stage. And part of the problem there, that huge black-box warnings is they're not specific to tumor. They attack peripheral nerve, for example.

所以是的，我認為你是對的。有幾種抗聚醣抗體已達到商業化階段。問題的一部分是，巨大的黑匣子警告並不是針對腫瘤的。例如，它們攻擊周圍神經。

And what I believe you're hearing today in Stephen's part of the presentation is that our platform is delivering what you might expect. It's glycans you can't really find through molecular biology tricks. You just can't do it that easily with glycans, and they are fairly specific. And as you point out, we have a very nice IgG antibody recognizing that glycan simultaneously.

我相信您今天在斯蒂芬的演講部分中聽到的是，我們的平台正在提供您可能期望的東西。這是你無法通過分子生物學技巧真正找到的聚醣。你不能用聚醣那麼容易地做到這一點，而且它們相當具體。正如您所指出的，我們有一種非常好的 IgG 抗體，可以同時識別該聚醣。

Great, thanks for taking my question, gentlemen.

太好了，謝謝您提出我的問題，先生們。

Thanks, Stephen.

謝謝，斯蒂芬。

Kemp Dolliver, Brookline.

坎普·多利弗，布魯克萊恩。

Thank you. I have a couple of questions there. Some of them are pointed in quick and I'll be respectful of your time. But quickly with regard to the incremental enrollment, what would be the assumed data cutoff to make a decision in the timeframe you're thinking?

謝謝。我有幾個問題。其中一些很快就會被指出，我會尊重您的時間。但是，關於增量註冊，在您考慮的時間範圍內做出決定的假設數據截止時間是多少？

So yes, so obviously, we're going to enroll and collect data until the study comes to fruition. I think we will report on the -- when it's appropriate by the end of the year of what our most up-to-date results would be. And I think the data cutoff of that typically requires a few weeks for us to be able to analyze the data and put it together. But --

所以，是的，很明顯，我們將招募並收集數據，直到研究取得成果。我認為我們將在年底前適當的時候報告我們的最新結果。我認為數據截止通常需要幾週的時間，我們才能分析數據並將其整合在一起。但 -

Yes, I think maybe one of the challenges you might be alluding to, and I think it's an important one is having sufficient follow-up to able to assess durability of response. So I think it might be a little bit easier in a way to make a no-go decision than it is a go decision. The no-go decision would be based on not seeing a level of activity for a given indication or the program overall. That would lead you to not move forward in Phase 2.

是的，我認為您可能提到的挑戰之一，而且我認為重要的挑戰之一是進行足夠的後續行動，以便能夠評估響應的持久性。所以我認為，在某種程度上，做出不走的決定可能比做出走的決定更容易一些。不進行的決定將基於沒有看到給定適應症或整個計劃的活動水平。這會導致你無法在第二階段繼續前進。

A go-to Phase 2 decision is a clinical decision but it's also a business decision. And I think that you could imagine a scenario where you've got responders or long-term stable disease and you want to give a little bit more time before making the decision to pull the trigger on an expensive Phase 2 program.

第二階段的首選決策是臨床決策，但也是商業決策。我認為你可以想像這樣一種情況：你已經有了反應者或長期穩定的疾病，並且你想在決定啟動昂貴的第二階段計劃之前多花一點時間。

But I think our commitment is really to try to provide fairly regular update and get to a crisp decision by the end of this year, plus-minus when we basically don't want to leave the study just open, enrolling patients without making a decision to go to Phase 2, or possibly end program.

但我認為我們的承諾實際上是嘗試提供相當定期的更新，並在今年年底前做出明確的決定，正負是當我們基本上不想讓研究處於開放狀態，在不做出決定的情況下招募患者進入第二階段，或者可能結束計劃。

I think we all feel pretty encouraged by the data that we're seeing, the durability of the responses, the PFS that seems to favor patients who express target. But I also think it's important for us to get to a decision because there's an opportunity cost here when you look at the other molecules that we have that are going to IND in the next 18 months.

我認為我們看到的數據、反應的持久性以及似乎有利於表達目標的患者的 PFS 都讓我們感到非常鼓舞。但我也認為做出決定對我們來說很重要，因為當你考慮我們擁有的將在未來 18 個月內進行 IND 的其他分子時，這裡存在機會成本。

I will stop there, thank you.

我就到此為止，謝謝。

Okay. Great. Well, thanks a lot. Much appreciate it, Kemp.

好的。偉大的。嗯，非常感謝。非常感謝，坎普。

Thanks, everyone, for your questions today and for joining the call. And I look forward to additional updates in the future.

謝謝大家今天提出的問題並加入電話會議。我期待未來的更多更新。

Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.

謝謝。今天的電話會議到此結束。感謝您的參與。您現在可以斷開連接。