Xencor Inc (XNCR) 2022 Q4 法說會逐字稿

Good afternoon. Thank you for standing by, and welcome to Xencor's Fourth Quarter and Year-End 2022 Conference Call. (Operator Instructions) Please be advised that this call is being recorded at the company's request.

下午好。感謝您的支持，歡迎來到 Xencor 的 2022 年第四季度和年終電話會議。 （操作員說明）請注意，此通話是應公司要求進行錄音的。

Now I would like to turn the call to your speaker today, Charles Liles, Head of Corporate Communications and Investor Relations. Sir, please go ahead.

現在，我想把電話轉給今天的發言人，企業傳播和投資者關係主管查爾斯·萊爾斯 (Charles Liles)。先生，請繼續。

Thank you, and good afternoon. Earlier today, we issued a press release which outlines the topics we plan to discuss today. The press release is available at www.xencor.com.

謝謝，下午好。今天早些時候，我們發布了一份新聞稿，概述了我們今天計劃討論的主題。新聞稿可在 www.xencor.com 上獲取。

With me on the call are Bassil Dahiyat, President and Chief Executive Officer; Allen Yang, Chief Medical Officer; John Desjarlais, Chief Scientific Officer; and John Kuch, Chief Financial Officer. After we make a few comments, we will then open up the call for your questions.

與我通話的是總裁兼首席執行官 Bassil Dahiyat；首席醫療官 Allen Yang； John Desjarlais，首席科學官；和首席財務官 John Kuch。在我們發表一些評論之後，我們將打開您的問題電話。

Before we begin, I would like to remind you that during the course of this conference call, Xencor management may make forward-looking statements, including statements regarding the company's future financial and operating results, future market conditions, the plans and objectives of management, future operations, the company's partnering efforts, capital requirements, future product offerings and research and development programs.

在我們開始之前，我想提醒您，在本次電話會議期間，Xencor 管理層可能會做出前瞻性陳述，包括有關公司未來財務和經營業績、未來市場狀況、管理層計劃和目標的陳述，未來的運營、公司的合作努力、資本需求、未來的產品供應和研發計劃。

These forward-looking statements are not historical facts, but rather are based on our current expectations and beliefs and are based on information currently available to us. Outcome of the events described in these forward-looking statements are subject to known and unknown risks, uncertainties and other factors that could cause actual results to differ materially from the results anticipated by these forward-looking statements, including, but not limited to, those factors contained in the Risk Factors section of our most recently filed annual report on Form 10-K and quarterly report on Form 10-Q.

這些前瞻性陳述不是歷史事實，而是基於我們當前的預期和信念，並基於我們目前可獲得的信息。這些前瞻性陳述中描述的事件的結果受已知和未知的風險、不確定性和其他因素的影響，這些因素可能導致實際結果與這些前瞻性陳述中預期的結果存在重大差異，包括但不限於那些我們最近提交的 10-K 表格年度報告和 10-Q 表格季度報告的風險因素部分中包含的因素。

With that, I'll pass the call over to Bassil.

有了這個，我會把電話轉給 Bassil。

Thanks, Charles, and good afternoon, everyone. We've used our array of modular approach and engineering tools to create our internal development portfolio in oncology and autoimmune disease, and we use the breadth of this portfolio to take multiple simultaneous shots on goal in the clinic.

謝謝，查爾斯，大家下午好。我們已經使用我們的一系列模塊化方法和工程工具來創建我們在腫瘤學和自身免疫性疾病方面的內部開發組合，我們利用這個組合的廣度在臨床上同時對目標進行多次射擊。

Our intent is to use proof-of-concept data from our early-stage studies to guide which programs we advance, which we terminate and which we partner so that we can use our resources on programs with the greatest potential for success and make room in our portfolio for the next wave of XmAb bispecifics and engineered cytokines. In addition, we use revenues from our partnership portfolio to support our development work.

我們的目的是使用來自我們早期研究的概念驗證數據來指導我們推進哪些項目、終止哪些項目以及與哪些項目合作，以便我們可以將我們的資源用於最有可能取得成功的項目，並為未來騰出空間我們下一波 XmAb 雙特異性抗體和工程細胞因子的產品組合。此外，我們使用合作夥伴組合的收入來支持我們的開發工作。

Here's a few pipeline highlights from 2022. For vudalimab, we continued our Phase II study in metastatic castration-resistant prostate cancer in combination with standard chemotherapy or PARP inhibitor. And we initiated a monotherapy Phase II in mCRPC and in gynecologic tumors, which are just some of the tumor types for PD-1 and CTLA-4 bispecifics to have potential.

以下是 2022 年的一些管線亮點。對於 vudalimab，我們繼續進行轉移性去勢抵抗性前列腺癌聯合標準化療或 PARP 抑製劑的 II 期研究。我們在 mCRPC 和婦科腫瘤中啟動了 II 期單一療法，這些只是 PD-1 和 CTLA-4 雙特異性藥物具有潛力的一些腫瘤類型。

And in November, we reported encouraging single-ascending dose data for XmAb564, a regulatory T cell targeted IL-2 for autoimmune disease, particularly the strong durability of Treg expansion. As a consequence, we started the multiple ascending dose study in atopic dermatitis and psoriasis patients to explore extended dosing regimens. We hope to have the psoriasis arms of the study finished by early 2024.

在 11 月，我們報告了令人鼓舞的 XmAb564 單劑量遞增數據，這是一種針對 IL-2 的調節性 T 細胞，用於自身免疫性疾病，特別是 Treg 擴增的強大持久性。因此，我們開始在特應性皮炎和銀屑病患者中進行多次遞增劑量研究，以探索延長給藥方案。我們希望在 2024 年初完成銀屑病研究。

And we started Phase I studies for 2 novel T cell engaging bispecifics. The first with XmAb819, which targets CD3 and ENPP3, an antigen and renal cell carcinoma that was built with our -- that was -- and we built the molecule with our 2+1 format for improved tumor selectivity. We believe 819 offers a new mechanism against a barely explored target with a high unmet need in second and later-line RCC.

我們開始了 2 種新型 T 細胞接合雙特異性藥物的 I 期研究。第一個是 XmAb819，它靶向 CD3 和 ENPP3，這是一種用我們構建的抗原和腎細胞癌 - 那是 - 我們用我們的 2 + 1 格式構建分子以提高腫瘤選擇性。我們相信 819 提供了一種新機制來應對二線和後續 RCC 中具有高度未滿足需求的幾乎未探索的目標。

The second T cell engager to start clinical studies was XmAb808, our first CD28-targeting bispecific. It co-stimulates T cells when it's bound to its tumor target, B7-H3, a widely expressed solid tumor antigen. Exciting early data for CD28 bispecifics has increased our already high enthusiasm to develop this new class of immunotherapies.

第二個開始臨床研究的 T 細胞接合劑是 XmAb808，這是我們的第一個 CD28 靶向雙特異性抗體。當它與其腫瘤靶標 B7-H3（一種廣泛表達的實體瘤抗原）結合時，它會共同刺激 T 細胞。令人興奮的 CD28 雙特異性早期數據增加了我們開發這類新型免疫療法的熱情。

And we're continually building the next wave of drug candidates with our engineering tools and try to tackle new or hard-to-address biology with them. Two such programs are advancing this year, led by the expected Phase I initiation for our third reduced potency cytokine, XmAb662, an engineered IL-12; and followed by IND filing for XmAb541, a 2+1 CD3 bispecific targeting CLDN6 for ovarian cancer.

我們正在不斷地使用我們的工程工具構建下一波候選藥物，並嘗試用它們來解決新的或難以解決的生物學問題。今年有兩個這樣的項目正在推進，其中以我們的第三個低效細胞因子 XmAb662（一種工程化 IL-12）的預期 I 期啟動為首；隨後提交了 XmAb541 的 IND 申請，這是一種針對 CLDN6 的 2+1 CD3 雙特異性抗體，用於治療卵巢癌。

[The 4 are] the well-balanced portfolio of late and early stage programs in development that we can potentially advance to approval and ultimately the market if the data supports it. Our development pipeline gets strong support from our broad line portfolio, not just from the revenues it generates, but also from the resources of our co-development partners for those programs that we have partnered.

[這 4 個是] 處於開發階段的後期和早期項目的均衡組合，如果數據支持，我們有可能提前批准並最終推向市場。我們的開發管道得到了我們廣泛的產品組合的大力支持，不僅來自它產生的收入，還來自我們合作開發的項目的共同開發合作夥伴的資源。

Now the last of my remarks is that we are in the midst of completing our laboratory and office relocation to Pasadena, where our new facility can accommodate our expanded R&D efforts and will help keep us at the cutting edge of protein engineering.

現在我要說的最後一點是，我們正在完成我們的實驗室和辦公室搬遷到帕薩迪納的工作，我們的新設施可以容納我們擴大的研發工作，並將幫助我們保持在蛋白質工程的前沿。

With that, I'll turn the call over to Allen Yang, our Chief Medical Officer, who will review recent updates from a few of our ongoing clinical studies for wholly owned programs.

有了這個，我將把電話轉給我們的首席醫療官 Allen Yang，他將審查我們正在進行的一些全資項目臨床研究的最新更新。

Thanks, Bassil. Vudalimab is our most advanced dual checkpoint inhibitor. We've designed the class of bispecific to bind T cells that express both targets, in this case, PD-1 and CTLA-4, with the intent to limit the exposure of the molecule to control and improve tolerability and yet still hit the cells that are going to be the most active against tumor.

謝謝，巴西爾。 Vudalimab 是我們最先進的雙重檢查點抑製劑。我們設計了一類雙特異性抗體來結合表達兩個靶標的 T 細胞，在本例中為 PD-1 和 CTLA-4，目的是限制分子的暴露以控制和提高耐受性，同時仍然攻擊細胞這將是最活躍的抗腫瘤藥物。

Two ongoing Phase II studies are looking for clinical signals that would prompt us to invest in registrational studies. At the SITC meeting in November, we reported the first data coming from our first Phase II study in combination with chemotherapy in patients with late-line metastatic castrate-resistant prostate cancer, a very high unmet need population.

兩項正在進行的 II 期研究正在尋找能夠促使我們投資於註冊研究的臨床信號。在 11 月的 SITC 會議上，我們報告了來自我們的第一個 II 期研究的第一批數據，該研究聯合化療治療晚期轉移性去勢抵抗性前列腺癌患者，這是一個非常高的未滿足需求人群。

Given the changing treatment landscape in prostate cancer, we designed the study to address several groups of prostate cancer patients, including aggressive variant, PARP actionable, PARP inhibitor relapse and MSI and a biomarker-negative group. We designed each arm to receive vudalimab and in combination with the standard therapy, if warranted.

鑑於前列腺癌的治療前景不斷變化，我們設計了這項研究來解決幾組前列腺癌患者，包括侵襲性變異、PARP 可操作、PARP 抑製劑復發和 MSI 以及生物標誌物陰性組。我們將每隻手臂設計為接受 vudalimab 並在必要時與標準療法相結合。

For chemotherapy-eligible subjects, we originally designed the study to use taxane platinum doublet based on a previously reported study that showed a high response rate in order to maximize potential efficacy. In the first patients, we saw multiple PSA50 drops in 3 of 8 patients, and 1 of these 8 patients had a durable partial response.

對於符合化療條件的受試者，我們最初設計的研究是根據先前報導的一項研究顯示高反應率以使用紫杉烷鉑雙藥，以最大限度地提高潛在療效。在第一批患者中，我們看到 8 名患者中有 3 名 PSA50 多次下降，這 8 名患者中有 1 名出現了持久的部分反應。

We also saw toxicity related to the intensive chemotherapy combination, but without a consistent type of AE among all the patients. However, we modified the chemotherapy dosing regimens, keeping vudalimab dosing as planned, and we're rolling again into the chemotherapy combination cohorts of the study.

我們還看到了與強化化療組合相關的毒性，但在所有患者中沒有一致的 AE 類型。然而，我們修改了化療劑量方案，保持 vudalimab 劑量按計劃進行，我們再次進入研究的化療聯合隊列。

The second Phase II study is evaluating vudalimab monotherapy in additional high-risk populations of prostate cancer as we continue to search for a defined subpopulation that we could advance quickly towards registration. The study is also enrolling patients with gynecological tumors, where we also saw good activity.

第二項 II 期研究正在評估 vudalimab 單藥治療在其他高危前列腺癌人群中的作用，因為我們將繼續尋找我們可以快速推進註冊的明確亞群。該研究還招募了婦科腫瘤患者，我們也看到了良好的活動。

And finally, this study introduces the flat dosing and more convenient schedule. Now as we continue to enroll these patients, we see a lot of opportunity for the program as emerging data across the class provides us signs for broad utility across additional solid tumor types.

最後，本研究介紹了平坦劑量和更方便的時間表。現在，隨著我們繼續招募這些患者，我們看到該計劃有很多機會，因為整個類別的新興數據為我們提供了在其他實體腫瘤類型中廣泛應用的跡象。

Now secondly, XmAb808 represents a new class of bispecific antibody targeting the CD28 pathway, and Xencor is among the first companies to enter the clinic with a molecule in this space. Clinical data beginning to emerge have indicated dramatically enhanced activity of a checkpoint inhibitor in prostate cancer, where previously checkpoint inhibitors have had limited activity. So we're seeing the case that a targeted CD28 bispecific, in this case, PSMA markedly increase the activity of a checkpoint inhibitor and serves as an important validation for the class.

其次，XmAb808 代表了一類新的針對 CD28 通路的雙特異性抗體，Xencor 是首批在該領域使用分子進入臨床的公司之一。開始出現的臨床數據表明，檢查點抑製劑在前列腺癌中的活性顯著增強，而此前檢查點抑製劑的活性有限。所以我們看到了靶向 CD28 雙特異性的案例，在這種情況下，PSMA 顯著增加了檢查點抑製劑的活性，並作為該類別的重要驗證。

We find the data encouraging enough to accelerate our own program targeting B7-H3, an antigen heavily expressed in multiple tumor types, including prostate cancer, renal cancer, lung cancer and many others. As B7-H3 is also expressed at low levels on some healthy tissues, we've incorporated our 2+1 bispecific technology into XmAb808 to potentially increase the therapeutic window.

我們發現這些數據令人鼓舞，足以加速我們自己針對 B7-H3 的計劃，B7-H3 是一種在多種腫瘤類型中大量表達的抗原，包括前列腺癌、腎癌、肺癌和許多其他腫瘤。由於 B7-H3 在一些健康組織中也以低水平表達，我們已將我們的 2+1 雙特異性技術整合到 XmAb808 中，以潛在地增加治療窗口。

And we're moving rapidly with XmAb808. The first patient in our Phase I dose escalation study was dosed last year. And following initial doses of XmAb808, we add pembrolizumab as combination therapy. We believe we are well positioned in the CD28 bispecific space, especially as there becomes increasing recognition that this class holds a lot of opportunity and is really starting to heat up. Not only with our XmAb808, but as our research teams advance more CD28 programs through preclinical development, we hope to share more in the coming months.

我們正在快速推進 XmAb808。我們 I 期劑量遞增研究中的第一位患者去年接受了給藥。在初始劑量的 XmAb808 之後，我們添加了 pembrolizumab 作為聯合療法。我們相信我們在 CD28 雙特異性領域處於有利地位，尤其是隨著人們越來越認識到這一類別擁有很多機會並且真正開始升溫。不僅是我們的 XmAb808，隨著我們的研究團隊通過臨床前開發推進更多 CD28 項目，我們希望在未來幾個月分享更多。

With that, I'll now hand over the call to John Desjarlais, our Chief Scientific Officer, to review 2 programs we plan to bring forward in the clinical development this year -- into clinical development this year: our IL-12 cytokine, XmAb662; and CLDN6 x CD3 bispecific, XmAb541.

有了這個，我現在將把電話轉給我們的首席科學官 John Desjarlais，審查我們計劃在今年臨床開發中推進的 2 個項目——今年進入臨床開發：我們的 IL-12 細胞因子 XmAb662 ;和 CLDN6 x CD3 雙特異性 XmAb541。

Thanks, Allen. So the key to all of our cytokine programs, including XmAb662, is that we reduced the potency, dialing down the receptor binding affinity to smooth out the activity profile observed in wild-type cytokines, which are natively very hot. And when administered systemically, it can generate a lot of immune toxicities and get cleared quickly.

謝謝，艾倫。因此，我們所有細胞因子項目（包括 XmAb662）的關鍵在於，我們降低了效力，調低了受體結合親和力，以平滑在天然非常熱的野生型細胞因子中觀察到的活性特徵。當全身給藥時，它會產生大量免疫毒性並迅速被清除。

Now IL-12 is a different kind of cytokine compared to IL-15 and IL-2. Instead of expanding T cells and NK cells, IL-2 promotes high levels of interferon gamma secretion, which increases the cytotoxicity of T cells and NK cells that makes tumor antigens more visible to the immune system.

現在，與 IL-15 和 IL-2 相比，IL-12 是一種不同的細胞因子。 IL-2 不是擴增 T 細胞和 NK 細胞，而是促進高水平的干擾素 γ 分泌，這會增加 T 細胞和 NK 細胞的細胞毒性，從而使免疫系統更容易識別腫瘤抗原。

So XmAb662 is a reduced potency IL-12 engineered with an XmAb bispecific Fc domain, enhanced with our Xtend technology to further duration of action. And the preclinical testing was reduced potency Fc fusion compared -- or native IL-12 Fc fusion demonstrated an improved pharmacokinetic profile of therapeutic window with superior exposure, a more gradual dose response and more sustained interferon gamma response. Our IND application was recently submitted and allowed by the FDA, and we look forward to initiating a Phase I study in patients with advanced solid tumors midyear.

因此，XmAb662 是一種效力降低的 IL-12，採用 XmAb 雙特異性 Fc 域設計，並通過我們的 Xtend 技術得到增強，以延長作用時間。與臨床前測試相比，Fc 融合降低了效力——或天然 IL-12 Fc 融合證明了治療窗口的藥代動力學特徵得到改善，具有更好的暴露、更漸進的劑量反應和更持久的干擾素伽馬反應。我們的 IND 申請最近提交並獲得 FDA 的批准，我們期待在年中啟動針對晚期實體瘤患者的 I 期研究。

Finally, XmAb541 is a CLDN6 x CD3 bispecific antibody built with our XmAb 2+1 format for improved tumor selectivity, and we are developing the molecule for patients with ovarian cancer. We are wrapping up IND-enabling studies and plan to submit an IND later this year.

最後，XmAb541 是一種 CLDN6 x CD3 雙特異性抗體，採用我們的 XmAb 2+1 格式構建，可提高腫瘤選擇性，我們正在為卵巢癌患者開發該分子。我們正在結束支持 IND 的研究，併計劃在今年晚些時候提交 IND。

Now a quick refresher on the XmAb 2+1 format where we build a bispecific or multi-specific using 2 tumor binding arms and 1 T cell binding arm. This is the approach we use to address a frequent observation with tumor targets that are also expressed on normal tissue. The therapy is intended to address solid tumors, off-target effects can lead to high toxicity.

現在快速回顧一下 XmAb 2+1 格式，我們使用 2 個腫瘤結合臂和 1 個 T 細胞結合臂構建雙特異性或多特異性抗體。這是我們用來解決對也在正常組織上表達的腫瘤靶標進行頻繁觀察的方法。該療法旨在解決實體瘤，脫靶效應可導致高毒性。

By having 2 antigen binding domains, we can tune the affinity for tumor antigen and bias the molecules to cells that have a lot of the antigen expressed over normal cells that have lower antigen expression where it's just harder to stick. We believe XmAb 2+1 could be generally applicable to bispecific antibodies against solid tumor targets and hope it opens the doors to bringing more CD3 cytotoxics and CD28 co-stimulators into development.

通過擁有 2 個抗原結合結構域，我們可以調整對腫瘤抗原的親和力，並使分子偏向於具有大量抗原表達的細胞，而正常細胞具有較低的抗原表達，更難粘附。我們相信 XmAb 2+1 可能普遍適用於針對實體瘤靶點的雙特異性抗體，並希望它能為開發更多 CD3 細胞毒劑和 CD28 共刺激劑打開大門。

Now with that, I'd like to hand the call over to John Kuch, our CFO, to review our financial results. John?

現在，我想將電話轉交給我們的首席財務官 John Kuch，以審查我們的財務業績。約翰？

Thank you, John. Xencor's broad portfolio of partnerships, collaborations and licenses continue to generate strong cash flow to support our operations. In 2022, we received $198.7 million in royalties and milestone payments, which helped fund our investments in our portfolio of bispecific and cytokine drug candidates.

謝謝你，約翰。 Xencor 廣泛的合作夥伴關係、合作和許可組合繼續產生強大的現金流來支持我們的運營。 2022 年，我們收到了 1.987 億美元的特許權使用費和里程碑付款，這有助於資助我們對雙特異性和細胞因子候選藥物組合的投資。

Total proceeds received in 2022 offset a substantial amount of our operating expenses, and we ended up 2022 with cash, cash equivalents, receivables and marketable debt securities of $613.5 million compared to $664.1 million at the end of 2021.

2022 年收到的總收益抵消了我們的大部分運營費用，到 2022 年，我們的現金、現金等價物、應收賬款和有價債務證券為 6.135 億美元，而 2021 年底為 6.641 億美元。

Based on current operating plans, we expect to have cash to fund research and development programs and operations through the end of 2025. And we currently estimate we will end 2023 with between $425 million and $475 million of cash, cash equivalents, receivables and marketable debt securities.

根據目前的運營計劃，我們預計到 2025 年底，我們將有現金為研發項目和運營提供資金。我們目前估計，到 2023 年底，我們將擁有 4.25 億美元至 4.75 億美元的現金、現金等價物、應收賬款和有價債務證券。

I refer you to our press release this afternoon and our 2022 Form 10-K filing for further information about our recent financial results.

請參閱我們今天下午的新聞稿和我們的 2022 年 10-K 表格文件，以了解有關我們最近財務業績的更多信息。

With that, we would now like to open up the call for questions. Operator?

有了這個，我們現在想打開問題的電話。操作員？

(Operator Instructions) Our first question will come from Mara Goldstein of Mizuho.

（操作員說明）我們的第一個問題將來自瑞穗的 Mara Goldstein。

I wanted to ask a question on 564 and the program there. And I'm really trying to understand, I guess, maybe when -- in looking at atopic dermatitis and psoriasis, what you think the benchmarks for success are going to be in terms of being able to advance that product forward?

我想問一個關於 564 和那裡的程序的問題。我真的想了解，我想，也許什麼時候——在研究特應性皮炎和牛皮癬時，你認為成功的基準是能夠推動該產品向前發展？

Yes. Thanks, Mara. For us, right now, there's 2 goals from this Phase Ib multiple ascending dose study that we're doing. First and foremost is establish a dosing regimen that we can move forward with, and that means someone that's safe and one that gives us good coverage of the target or rather a good biomarker movement of the Tregs for the duration of our dosing interval. So that's step 1. And I think those 2 indications are great indications for that because you can see, looking at skin, how the disease readout is doing in parallel with your biomarkers. So that's goal one.

是的。謝謝，瑪拉。對我們來說，現在，我們正在進行的 Ib 期多次遞增劑量研究有 2 個目標。首先也是最重要的是建立一個我們可以繼續推進的給藥方案，這意味著一個安全的人，一個可以讓我們很好地覆蓋目標的人，或者更確切地說，在我們的給藥間隔期間，Tregs 的良好生物標誌物運動。所以這是第 1 步。我認為這 2 個適應症是很好的適應症，因為你可以看到，看著皮膚，疾病讀數如何與你的生物標誌物同時進行。這就是目標一。

I think would -- the second goal addresses your question of what's the benchmark for success. I would say in both of those indications, they're generally high. I will say that the thing we're going to be keying off of is looking at how durable and how long of an effect we can have with the agent. Does this have new biology by attacking Tregs that you can extend response time even beyond dosing duration that was seen with some competitor programs, glimmers of it? And how long of a dosing interval can we get? Can we build a best-in-class dosing interval, extending beyond every 2 weeks that a lot of the competing programs seem to have settled into?

我認為——第二個目標解決了你關於成功的基準是什麼的問題。我會說，在這兩個跡像中，它們通常都很高。我要說的是，我們要重點關注的是我們可以對代理產生的影響有多持久和多長時間。這是否通過攻擊 Tregs 具有新的生物學特性，您可以延長響應時間，甚至超過一些競爭對手程序中看到的給藥持續時間，微光？我們可以獲得多長時間的給藥間隔？我們能否建立一流的給藥間隔，延長到許多競爭項目似乎已經適應的每 2 週一次？

So I think those are the questions that we want to address with this early study. And then I think after that, there's good benchmarks for CASI and for easy scores.

所以我認為這些是我們想要通過這項早期研究解決的問題。然後我認為在那之後，CASI 和簡單的分數就有了很好的基準。

Okay. And if I can just ask on vudalimab. The discussion around reengaging the trial now that you finished modifying the protocol, can you talk a little bit about just the enrollment characteristics for that program?

好的。如果我可以問一下 vudalimab。既然你們已經完成了協議的修改，關於重新參與試驗的討論，你能談談這個項目的註冊特徵嗎？

You mean how well it's enrolling?

你的意思是它的註冊情況如何？

And what those dynamics have been? Yes, with those dynamics, like what you can expect going forward? Do you think you'll go back to sort of baseline where you were?

這些動力是什麼？是的，有了這些動力，就像你可以期待的那樣？你認為你會回到你原來的那種基線嗎？

I don't know. Allen, do you want to comment on that?

我不知道。艾倫，你想對此發表評論嗎？

Yes. So just to be clear, Mara, we have 2 Phase IIs. We have a monotherapy Phase II, which explores a sort of new flat dosing and schedule, and that we've clinically defined sort of an aggressive type of prostate cancer. And then we have the first Phase II, which actually molecularly defines different subgroups of prostate cancer. This data is available, but we have an aggressive variance subtype. We have a PARP enable -- sort of a PARP actionable subtype, a PARP inhibitor, sort of relapsed/refractory group, micro-satellite unstable group and then finally, everybody else.

是的。所以要明確一點，Mara，我們有 2 個 II 期。我們有一個單一療法的 II 期，它探索了一種新的平坦劑量和時間表，並且我們已經在臨床上定義了一種侵襲性類型的前列腺癌。然後我們有第一個 II 期，它實際上在分子上定義了前列腺癌的不同亞組。此數據可用，但我們有一個激進的方差子類型。我們有一個 PARP 啟用 - 一種 PARP 可操作亞型，一種 PARP 抑製劑，一種複發/難治組，微衛星不穩定組，最後是其他所有人。

And I guess what you're asking is how they're enrolling. Now that we had to pause to just the chemotherapy groups, and that was 3 of the groups, but the other groups continue to enroll. And now we've opened up the other arms with chemotherapy, and we've modified the chemotherapy for 2 of those groups.

我猜你問的是他們是如何註冊的。現在我們不得不暫停化療組，那是其中的 3 個組，但其他組繼續招募。現在我們已經用化學療法打開了另一組，我們已經修改了其中兩個組的化學療法。

Our next question will come from Edward Tenthoff of Piper Sandler.

我們的下一個問題將來自 Piper Sandler 的 Edward Tenthoff。

I wanted to get a sense, again, to the extent you can share, sort of how the profile of the CD28 is differing from CD3. And as you sort of advance on the pipeline, how do you see prioritizing one mechanism versus the other? Are there places where one may make more sense?

我想再次了解一下，在您可以分享的範圍內，CD28 的配置文件與 CD3 有何不同。隨著您在管道上取得進展，您如何看待優先考慮一種機製而不是另一種機制？有什麼地方更有意義嗎？

There's multiple facets to that one. John, why don't you take the point about refreshing on the differential biology of CD28 and CD3 and what we can do with that? And maybe I'll jump in on the second one.

這個有多個方面。約翰，你為什麼不談談關於更新 CD28 和 CD3 的差異生物學以及我們可以用它做什麼的觀點？也許我會加入第二個。

Yes, sure. Yes, thanks for the questions, Ed. So the way we think about the CD3 versus CD28 is with the CD3, it's basically more of an artificial immunity where you're just taking advantage of any T cell around engaging it through CD3 and recruiting it to attack the tumor cells.

是的，當然。是的，謝謝你的問題，埃德。所以我們考慮 CD3 和 CD28 的方式是 CD3，它基本上更像是一種人工免疫，你只是利用任何 T 細胞通過 CD3 與其結合併招募它來攻擊腫瘤細胞。

With the CD28, because it's just providing Signal 2, that's equally intriguing biology because now that Signal 2 has to build off of an endogenous Signal 1, which comes from a neoantigen T cell recognition by the T cells. And of course, when you're applying the CD28, in order to fully open up that Signal 1, you're generally going to be combining with a PD-1 checkpoint blockade.

對於 CD28，因為它只是提供信號 2，所以這同樣是有趣的生物學，因為現在信號 2 必須建立在內源性信號 1 的基礎上，而內源性信號 1 來自 T 細胞對新抗原 T 細胞的識別。當然，當你應用 CD28 時，為了完全打開信號 1，你通常會結合 PD-1 檢查點封鎖。

So -- and then the sort of the third arm of that is we also see really interesting opportunity for combining the CD3s with the CD28s. And that's one of the reasons we chose B7-H3 as our sort of flagship CD28 program because it's expressed in so many different histologies, it could be sort of a one-size-fits-all combination partner for our CD3s or other people's CD3s.

所以——然後是第三種方式，我們也看到了將 CD3 與 CD28 結合起來的真正有趣的機會。這就是我們選擇 B7-H3 作為我們的旗艦 CD28 程序的原因之一，因為它以多種不同的組織學表達，它可能是我們的 CD3 或其他人的 CD3 的一種放之四海而皆準的組合夥伴。

Great. That's very helpful. Go ahead, Bassil. Sorry.

偉大的。這很有幫助。去吧，巴西爾。對不起。

Go ahead, Ed. Did you get all your answers? Do you need me to address your other point?

去吧，埃德。你得到所有的答案了嗎？您需要我解決您的其他問題嗎？

No, please, I was saying go ahead, Bassil.

不，拜託，我是說繼續，Bassil。

Yes. So regarding how we view the different MOAs and think about them in different indications, some of it depends on target availability. Is there an opportunity to improve response for targets that have been tried that have promising biology but didn't work out? I think that's the case where the combination of a CD28 with a checkpoint inhibitor could be very attractive. I think we've seen that from competitor programs in prostate cancer with that early glimmer of data.

是的。因此，關於我們如何看待不同的 MOA 並以不同的適應症來考慮它們，其中一些取決於目標可用性。是否有機會提高對那些已經嘗試過但沒有成功的生物學目標的反應？我認為在這種情況下，CD28 與檢查點抑製劑的組合可能非常有吸引力。我認為我們已經從前列腺癌的競爭項目中看到了這一點，以及早期的數據。

And then philosophically, on targets that you can -- you have a good, nice differential of expression, healthy to normal tissue, hitting it with that direct attack of a CD3 could make sense more, right? So that's generally how we think about it as we explore the initial biology of the CD28 over the next year or 2.

然後從哲學上講，在你能做到的目標上——你有一個很好的、很好的表達差異，對正常組織來說是健康的，用 CD3 的直接攻擊來擊中它可能更有意義，對吧？所以這就是我們在未來一兩年探索 CD28 的初始生物學時通常的想法。

Great. Excited for more data this year.

偉大的。對今年的更多數據感到興奮。

Thank you.

謝謝。

Our next question will come from Dane Leone of Raymond James.

我們的下一個問題將來自 Raymond James 的 Dane Leone。

Congrats on all the progress. I just wanted to get your take on maybe some of the earlier programs that you have emerging now. And firstly, maybe I would like to hear your updated thoughts on the IL-12 approach. There seems like there's been maybe a few more discontinuations from peer programs. Curious to your thoughts on how you're differentiating to create a therapeutic index essentially out of a difficult cytokine. And then maybe on targeting with B7-H3 versus maybe another emerging approach of using B7-H4 would be interesting as well.

祝賀所有的進步。我只是想听聽您對現在出現的一些早期計劃的看法。首先，也許我想听聽您對 IL-12 方法的最新想法。似乎還有一些同行計劃中止了。想知道您是如何從一個困難的細胞因子中區分出一個治療指數的。然後也許使用 B7-H3 與使用 B7-H4 的另一種新興方法進行定位也會很有趣。

So on the IL-12, I think it comes down to our reduced potency design is something that has given us significantly improved tolerability profiles versus wild-type level activity cytokines for IL-15 and IL-2 programs. So I think that's what we're banking on.

因此，在 IL-12 上，我認為這歸結為我們降低效力的設計使我們的耐受性與 IL-15 和 IL-2 程序的野生型水平活性細胞因子相比有了顯著改善。所以我認為這就是我們所依賴的。

Maybe, John, if you want to touch briefly on the preclinical profile and not even primate data we have for XmAb662 and how that we believe differentiates it.

也許，約翰，如果你想簡單地談談我們擁有的 XmAb662 的臨床前概況，甚至靈長類動物數據，以及我們認為它如何與眾不同。

Yes. Yes, in fact, thanks for the question, Dane. So we actually compare the wild-type IL-12 Fc fusion to our XmAb662, which again has around 100-fold potently reduced. And recall that the problem with these cytokines is when they signal, they actually get cleared through the receptors.

是的。是的，事實上，謝謝 Dane 的提問。因此，我們實際上將野生型 IL-12 Fc 融合與我們的 XmAb662 進行了比較，後者的效力再次降低了約 100 倍。回想一下，這些細胞因子的問題在於，當它們發出信號時，它們實際上會通過受體被清除。

And so when we look at monkeys at a wild-type IL-12 Fc, we dose it as high as we can in terms of tolerability, and it's gone in about 1 or 2 days. In contrast, XmAb662, because of its potency reduction, actually has a -- it looks incredibly like an antibody. It's got a halflife of 14 to 20 days in the monkeys. That's likely to extend out even further. So that's one aspect.

因此，當我們觀察猴子的野生型 IL-12 Fc 時，我們根據耐受性給予盡可能高的劑量，它會在大約 1 或 2 天內消失。相比之下，XmAb662，由於其效力降低，實際上具有 - 它看起來非常像抗體。它在猴子體內的半衰期為 14 到 20 天。這可能會延伸得更遠。所以這是一方面。

Bassil also mentioned that when you have the potency-reduced version, you have much greater tolerability. And then the thing in the monkey studies that kind of inspired me the most is when we put in the wild type IL-12 at a range -- a 30-fold differential dose range, and every one of those doses or dose levels gave the same exact initial peak of interferon-gamma response, irrespective of the dose.

Bassil 還提到，當您使用效力降低的版本時，您的耐受性會大得多。然後在猴子研究中給我啟發最大的事情是當我們將野生型 IL-12 置於一個範圍內時——一個 30 倍的差異劑量範圍，並且這些劑量或劑量水平中的每一個都給出了與劑量無關，干擾素-γ 反應的初始峰值完全相同。

The only thing that changed when you dose more was because you get a little more exposure, you broaden out that peak in terms of time. In contrast, with 662, we actually saw a really nice gradual increase of the dose response as we upped the dose. And I think that is going to give us a lot more flexibility to really zero in on the optimal dose and, therefore, therapeutic index.

當你服用更多劑量時，唯一發生變化的是因為你得到了更多的曝光，你在時間上拓寬了那個峰值。相比之下，對於 662，當我們提高劑量時，我們實際上看到了劑量反應非常好的逐漸增加。我認為這將為我們提供更大的靈活性，使我們真正將最佳劑量和治療指數歸零。

And regarding B7-H3 versus B7-H4, I think we'll focus on what we find attractive about B7-H3. It's expressed in multiple tumor types. It has a good differential across multiple tissues for tumor versus normal tissue. It's absent -- or very undetectable expression, I should say, in certain problematic tissues like the central nervous system, brain and nerves. So I think that makes it very attractive. The B7-H4 is a target I'm starting to see pop up, and I think there's very little data to comment on it.

關於 B7-H3 與 B7-H4，我認為我們將關注我們認為 B7-H3 有吸引力的地方。它在多種腫瘤類型中表達。對於腫瘤與正常組織，它在多個組織之間具有良好的差異。在某些有問題的組織（如中樞神經系統、大腦和神經）中，它不存在——或者說是非常檢測不到的表達。所以我認為這使它非常有吸引力。 B7-H4 是我開始看到的一個目標，我認為對此發表評論的數據很少。

Do you view B7-H3 in a different light when using a co-stim approach like CD28 versus the past few times you have used ADCs?

與過去幾次使用 ADC 相比，使用 CD28 等共刺激方法時，您是否從不同的角度看待 B7-H3？

I think it could be very, very different in immunotherapy approach versus delivering a direct -- delivering a cytotoxic could be profoundly different. And so I don't know how much read-through we get other than that you have clearly enough of that target around tumors that an ADC can provide activity. So beyond that, there are such different mechanisms that I don't know of anything we can glean.

我認為免疫治療方法與直接提供細胞毒性藥物可能會有很大不同——提供細胞毒性藥物可能會有很大不同。因此，我不知道除了您在腫瘤周圍有足夠清晰的靶標，ADC 可以提供活性外，我們還讀了多少。所以除此之外，還有如此不同的機制，我不知道我們能收集到什麼。

Our next question will come from Etzer Darout of BMO Capital Markets.

我們的下一個問題將來自 BMO Capital Markets 的 Etzer Darout。

First one is a few things going on in prostate. Just wanted to know if you had any updates on AMG 509, the STEAP1 2+1. Any updates here from Amgen on the development?

第一個是前列腺中發生的一些事情。只是想知道您是否有關於 AMG 509 STEAP1 2+1 的任何更新。 Amgen 對開發的任何更新？

And for XmAb808, just wondered for that program, the start of the sort of combo trial with pembrolizumab, is that just kind of based on literature examples and/or sort of preclinical data on the synergies or if that's something where you've seen something in the clinic that sort of prompted the combination with pembro?

對於 XmAb808，只是想知道該項目，開始與 pembrolizumab 進行的那種組合試驗，是否只是基於文獻示例和/或關於協同作用的臨床前數據，或者如果這是你已經看到的東西在診所裡，那種促使與 pembro 的組合？

Great. Regarding Amgen's AMG 509 program, which is licensed, they licensed all the tools and technologies from us to build it. The only information we can share is what they publicly announced. I think they did it at their earnings last month, and they said they expect to have initial data presentation in the second half of this year and that they're pursuing a quite broad Phase I program looking at both combinations, monotherapy, they've got a subcutaneous formulation in addition to their IV. So they're putting a lot of resource behind it. That's all we can share publicly. But we're certainly encouraged by the effort and by the initial data we saw a year ago.

偉大的。關於 Amgen 的 AMG 509 程序，該程序已獲得許可，他們從我們那裡獲得了構建它的所有工具和技術的許可。我們唯一可以分享的信息是他們公開宣布的信息。我認為他們在上個月的收益中做到了這一點，他們表示他們希望在今年下半年獲得初步數據，並且他們正在進行一項相當廣泛的 I 期計劃，著眼於兩種組合，單一療法，他們已經除了他們的靜脈注射外，還有一種皮下製劑。所以他們在背後投入了大量資源。這就是我們可以公開分享的全部內容。但我們確實對一年前看到的努力和初步數據感到鼓舞。

For 808, I think that there is a very strong theoretical reason. In fact, the fundamental basis for why you want to use a CD28 bispecific for combining it with either a checkpoint inhibitor or, say, a CD3 bispecific because that completes the circle of getting the CD28 to give you that potent signal to activation and maintenance of activation, while the other side, Signal 1 initiates that T cell movement. And so pembro is based on very strong theoretical data for that combo for why you want to combine a checkpoint inhibitor with a CD28 for that CD28 to put the checkpoint inhibitor over the hump when it's in a nominally cold tumor.

對於808，我認為有很強的理論依據。事實上，您想要使用 CD28 雙特異性抗體將其與檢查點抑製劑或 CD3 雙特異性抗體結合使用的根本原因在於，這完成了讓 CD28 為您提供激活和維持的有效信號的循環激活，而另一側，信號 1 啟動 T 細胞運動。因此，pembro 基於該組合的非常強大的理論數據，說明為什麼你想將檢查點抑製劑與 CD28 結合使用，以使該 CD28 在名義上冷的腫瘤中將檢查點抑製劑置於駝峰之上。

Yes. And Bassil, just to put a finer point on that, there's some pretty strong literature that the dominant mechanism of action of PD-1, the checkpoint itself, is to directly inhibit CD28 signaling, and most people also think it inhibits the Signal 1. And so the idea is that the B7-H3 CD28 by itself is going to be hindered unless you could also block PD-1 at the same time.

是的。而 Bassil，只是為了更好地說明這一點，有一些相當有力的文獻表明 PD-1（檢查點本身）的主要作用機制是直接抑制 CD28 信號，而且大多數人也認為它會抑制信號 1。所以這個想法是 B7-H3 CD28 本身會受到阻礙，除非你也可以同時阻止 PD-1。

And our next question will come from David Dai of SMBC.

我們的下一個問題將來自 SMBC 的 David Dai。

Congrats on the progress. So I have 2 questions. First is just on vudalimab. We have seen some competitors showing PD-1 and CTLA-4 as if -- especially if antibody has some pretty intriguing data in metastatic prostate cancer at ASCO GI. Could you maybe compare and contrast to your vudalimab's drug profile versus the competitor PD-1 CTLA-4 antibodies?

祝賀進步。所以我有兩個問題。首先是在 vudalimab 上。我們已經看到一些競爭對手展示了 PD-1 和 CTLA-4——特別是如果抗體在 ASCO GI 上有一些非常有趣的轉移性前列腺癌數據。您能否將您的 vudalimab 的藥物概況與競爭對手的 PD-1 CTLA-4 抗體進行比較和對比？

Sure. So I guess for starters, I guess, we'll say there's a lot of movement in the PD-1 CTLA-4 class, it's starting to happen, also based on very early studies. And we're very encouraged by how that is reflecting on now the potential for these dual checkpoints as we start to sort out how to use them. I'll start off by saying that the relevant comparison is the monotherapy data from our Phase I expansion cohorts that we presented a while back compared to what was presented at ASCO GU. So it's that monotherapy-monotherapy comparison.

當然。所以我想對於初學者來說，我想，我們會說 PD-1 CTLA-4 類有很多變化，它開始發生，也是基於非常早期的研究。當我們開始理清如何使用它們時，我們對現在如何反映這些雙重檢查點的潛力感到非常鼓舞。我首先要說的是，相關比較是我們不久前展示的 I 期擴展隊列的單藥治療數據與 ASCO GU 上展示的數據相比。這就是單一療法與單一療法的比較。

So I don't know, Allen, did you want to touch on that?

所以我不知道，艾倫，你想談談這個嗎？

Yes, sure, Bassil, I'd be happy to. I mean I think the data at ASCO GU sort of validates the class in prostate cancer. And it's difficult to compare the data between our data and theirs. What we reported is a PSA response rate of about 20% in the heavily pretreated U.S. population, U.S.-only population, where the median number of therapies was 5.

是的，巴西爾，我很樂意。我的意思是我認為 ASCO GU 的數據在某種程度上驗證了前列腺癌的類別。而且很難比較我們的數據和他們的數據。我們報告的是，在經過大量預處理的美國人群中，PSA 反應率約為 20%，僅限美國人群，其中治療的中位數為 5。

The other data that was reported at ASCO GU reported a response rate -- a PSA response rate in the high 20%, but a less pretreated population where the median number of treatments was only 2. So again, I think it's interesting data. It supports the idea of doing these PD-1s, CTLA-4s in prostate cancer. And we already believe that, and that's why we started 2 Phase II programs and are moving aggressively to try to figure out a registration pathway.

在 ASCO GU 上報告的其他數據報告了響應率——PSA 響應率高達 20%，但預處理較少的人群中，治療的中位數僅為 2 次。因此，我再次認為這是有趣的數據。它支持在前列腺癌中進行這些 PD-1、CTLA-4 的想法。我們已經相信這一點，這就是為什麼我們啟動了 2 個 II 期項目，並正在積極行動以試圖找出註冊途徑。

Yes, got it. That's really helpful. And just another question on the plamotamab. I know you're currently developing a subcu version of the drug. Could you maybe talk a little bit more about the status of the subcu formulation? And when should we expect to see data from that program?

是的，明白了。這真的很有幫助。還有一個關於 plamotamab 的問題。我知道你目前正在開發這種藥物的亞微版本。您能否多談談 subcu 公式的狀態？我們應該在什麼時候看到該程序的數據？

So we initiated clinical studies at the dosed patients with the subcu formulation last quarter, and that is a dose escalation base study so we can figure out the subcu regimen, priming dose and step-up doses. We, of course, have all the information we have from the IV that we think is going to greatly accelerate that process relative to what we had learned from the IV. And of course, we're doing this in collaboration with our partner, Janssen.

因此，我們在上個季度對使用 subcu 製劑的患者進行了臨床研究，這是一項劑量遞增基礎研究，因此我們可以確定 subcu 方案、啟動劑量和遞增劑量。當然，我們擁有來自 IV 的所有信息，我們認為相對於我們從 IV 中學到的知識，這些信息將大大加速該過程。當然，我們正在與我們的合作夥伴 Janssen 合作進行這項工作。

So that's going forward as part of the whole package of our B-cell collaboration with Janssen, which also incorporates our CD28 bispecifics where we just, this quarter, announced that we have achieved the candidate selection milestones. So we've delivered the B-cell targeted CD28 that ultimately, when it gets to the clinic, would be combined with pembro -- sorry, with plamotamab. So that's the sort of general context. And we'll guide on data as we go forward with the caveat that, of course, Janssen has to be party to wanting to disclose data.

因此，這是我們與楊森 (Janssen) 合作的整個 B 細胞合作計劃的一部分，其中還包括我們的 CD28 雙特異性藥物，我們剛剛在本季度宣布我們已經實現了候選選擇里程碑。因此，我們已經交付了靶向 B 細胞的 CD28，最終，當它到達診所時，將與 pembro 結合——抱歉，與 plamotamab 結合。這就是一般背景。在我們前進的過程中，我們將指導數據，當然，Janssen 必須成為想要披露數據的一方。

Our next question will come from Charles Zhu of Guggenheim Partners.

我們的下一個問題將來自 Guggenheim Partners 的 Charles Zhu。

I have one question that's essentially a follow-up to something that Etzer had asked. But regarding XmAb808, encouraging to see that you guys are combining this with pembro. But perhaps given you have other pipeline assets in the clinic that are also going after prostate cancer with similar mechanisms such as vudalimab, how are you gauging the potential to, I guess, codevelop with vudalimab as opposed to an external asset? And how should we think about that?

我有一個問題，本質上是對 Etzer 提出的問題的跟進。但關於 XmAb808，令人鼓舞的是看到你們將其與 pembro 相結合。但也許鑑於您在診所中擁有其他管道資產，這些資產也在使用類似機制（如 vudalimab）治療前列腺癌，我想您如何衡量與 vudalimab 共同開發而不是外部資產的潛力？我們應該如何考慮？

We think that's a great idea and a great approach. We absolutely have it in our minds. As we escalate with 808, we want to obviously do that very quickly, and we have to start from relatively low levels because, of course, regulators are cautious with new immunotherapies.

我們認為這是一個好主意和好方法。我們絕對有它在我們的腦海裡。當我們升級 808 時，我們顯然希望非常快地做到這一點，我們必須從相對較低的水平開始，因為當然，監管機構對新的免疫療法持謹慎態度。

So as we escalate, we have, in our minds, how we can quickly flex in with our own pipeline agents such as vudalimab or perhaps even CD3 bispecifics or some of our CD3 bispecifics that could overlap with the expression patterns that it will hit are going to -- are moving forward, for example, XmAb819, our ENPP3.

因此，隨著我們升級，在我們的腦海中，我們如何能夠快速地使用我們自己的管道代理，例如 vudalimab 或什至 CD3 雙特異性藥物或我們的一些 CD3 雙特異性藥物，這些藥物可能與它將命中的表達模式重疊到——正在向前發展，例如，XmAb819，我們的 ENPP3。

So absolutely, I think the key here is rolling fast, try to understand data in light of a well-understood standard pembro where enrollment, frankly, is greatly facilitated by its broad use and jump in once we've got a little further.

所以絕對，我認為這裡的關鍵是快速滾動，嘗試根據一個易於理解的標準 pembro 來理解數據，坦率地說，它的廣泛使用極大地促進了註冊，一旦我們走得更遠就跳進去。

Our next question will come from Bill Maughan of Canaccord Genuity.

我們的下一個問題將來自 Canaccord Genuity 的 Bill Maughan。

So just looking at the cash guidance for this year and thinking through the fact that sotrovimab is still available in some ex U.S. jurisdictions, how much of sotrovimab are you expecting this year in that guidance? And then I'll have a follow-up...

因此，只要看看今年的現金指導，並考慮到 sotrovimab 在美國以外的一些司法管轄區仍然可用的事實，你在該指導中期望今年的 sotrovimab 有多少？然後我會有一個後續...

In '23?

在 23 年？

Yes.

是的。

In '23, 0. It's been coming down since Q1, and they lost their U.S. authorization in Q1. So it's just been ex U.S. So going forward, anything we get is found money. We have no expectations of future revenue.

在 23 年，0。自第一季度以來一直在下降，他們在第一季度失去了美國授權。所以它只是前美國所以向前看，我們得到的任何東西都是找到錢。我們對未來的收入沒有期望。

Great. And then on your 2+1 T cell engagers, so understanding that the differentiated mechanism allows you to go after something like a CD28. Do you see room to improve on more well-worn targets like CD3 over products that are later in development and kind of come in behind them and steal share with a better version of what's already kind of making it to market?

偉大的。然後在你的 2+1 T 細胞接合器上，了解差異化機制可以讓你追求像 CD28 這樣的東西。您是否看到有改進 CD3 等更老舊目標的空間，而不是開發後期開發的產品，有點落後於它們，並與已經上市的更好版本的產品搶奪份額？

Absolutely. We have all of that kind of consideration in mind. And we watch very carefully any CD3 programs that are advancing into the clinic. I would say it's still early days in the whole CD3 world. So there's not a lot of late-phase CD3 work yet outside of the heme malignancies where the CD20 CD3s and BCMA CD3 is dominating.

絕對地。我們考慮到了所有這些因素。我們非常仔細地觀察任何進入臨床的 CD3 項目。我會說整個 CD3 世界還處於早期階段。因此，除了 CD20 CD3 和 BCMA CD3 占主導地位的血紅素惡性腫瘤之外，還沒有很多晚期 CD3 研究。

And those don't strike us as maybe fruitful avenues to use this plan of attack as those are not solid tumors. But absolutely, we look at potential fast-follower approaches with the 2+1 carefully. I think the opportunity space is still just emerging, so that's why we haven't declared any yet.

那些並沒有讓我們覺得可能是使用這種攻擊計劃的富有成果的途徑，因為它們不是實體瘤。但絕對可以，我們會仔細研究 2+1 的潛在快速跟進方法。我認為機會空間仍剛剛出現，所以這就是我們尚未宣布的原因。

Our next question will come from Michael King of EF Hutton.

我們的下一個問題將來自 EF Hutton 的 Michael King。

Just to maybe pick up where Dane left off on IL-12. I just wondered, just as far as the cytokine space is concerned, sort of [writ] large, I'm a big fan of the engineered cytokine space. But I just wonder if we know enough, either as antagonists or agonists, what the real correlates or the real clues are to clinical success. It's nice to see gamma interferon levels go up in response to IL-12, but do we know what the meaning of that is?

只是為了繼續 Dane 在 IL-12 上中斷的地方。我只是想知道，就細胞因子空間而言，有點大，我是工程細胞因子空間的忠實粉絲。但我只是想知道我們是否足夠了解，無論是作為拮抗劑還是激動劑，臨床成功的真正關聯或真正線索是什麼。很高興看到 γ 干擾素水平隨著 IL-12 的升高而升高，但我們知道這意味著什麼嗎？

And I think it's kind of, again, especially important to think about in light of some of the recent developments, both in IL-12 and the IL-2 world. I just saw as this call -- literally as this call started, Nektar indicated that its REZPEG, all the solutions, had some activity in SLE, but did not achieve a clinically relevant, [stats-big] result. So do we know enough about this class to really put them in the clinic without further preclinical exploration?

而且我認為，考慮到 IL-12 和 IL-2 領域的一些近期發展，考慮這一點特別重要。我剛剛看到這個電話——從字面上看，當這個電話開始時，Nektar 表示它的 REZPEG，所有的解決方案，在 SLE 中都有一些活動，但沒有達到臨床相關的 [stats-big] 結果。那麼，我們是否足夠了解這一類，無需進一步的臨床前探索就可以真正將它們投入臨床？

There's no doubt that we don't have perfect knowledge about what it's going to take to succeed in cytokine. So I would say that's the case for pretty much almost any drug. I think with cytokines, we do know that a lot of the approaches that have been tried in the past have been challenged and have not worked.

毫無疑問，對於細胞因子的成功需要什麼條件，我們並不完全了解。所以我想說幾乎所有藥物都是如此。我認為對於細胞因子，我們確實知道過去嘗試過的許多方法都受到了挑戰並且沒有奏效。

And so I will say that we are taking a specific approach. We are putting a bet down on reduced potency cytokines, which inherently, because of that reduced potency, gives you longer action and a lower peak punch, which so far with 2 programs out of 2 has reduced tolerability issues, but still given this profound biomarker movement.

所以我會說我們正在採取一種特定的方法。我們押注效力降低的細胞因子，由於效力降低，它本質上會給你更長的作用和更低的峰值衝擊力，到目前為止，2 個程序中的 2 個程序已經減少了耐受性問題，但仍然考慮到這個深刻的生物標誌物移動。

So we think that's a great start. Does it answer the question fully, do we -- are we out of the risk window? Absolutely not. We're optimistic our IL-12 will share those kinds of properties on the biomarkers and the tolerability, but we're going to see, right, if our preclinical data plays out in humans. We'll start seeing that later this year.

所以我們認為這是一個很好的開始。它是否完全回答了這個問題，我們 - 我們是否超出了風險窗口？絕對不。我們很樂觀，我們的 IL-12 將在生物標誌物和耐受性上分享這些特性，但我們將看到，正確的，如果我們的臨床前數據在人類身上發揮作用。我們將在今年晚些時候開始看到這一點。

So we don't have the answers, but we've got a bet that so far is performing as it should, this reduced potency. And we think the opportunity is enormous if we could be among the first to crack that code. So it's absolutely a bet we think is worth taking. And I think the one thing we can hang our hat on is if you can see the immune markers of activity, that certainly ties in better to whether you're going to have success.

所以我們沒有答案，但我們可以打賭，到目前為止，這種降低的效力正在發揮應有的作用。我們認為，如果我們能率先破解該代碼，那麼機會是巨大的。因此，這絕對是我們認為值得的賭注。我認為我們可以確定的一件事是，如果你能看到活動的免疫標記，那肯定與你是否會取得成功有更好的聯繫。

We know wild-type IL-2, Proleukin, creates all sorts of immune markers of IL-2 activity, most of them toxic, but it also in a small number of patients can cure them. So I think that's all we've got. And I think how we position ourselves is really strong. And I will say referencing some of the recent REZPEG news, I will say that lupus is an area where many successful drugs have had unsuccessful fungal trials, and it's a challenging development space. Certainly, Xencor in its past has had some experiences with tricky conflicted Phase II data in lupus. And so we'll dig into that more, but it's a hard read-through on a lupus Phase II really to anything, I would say.

我們知道野生型 IL-2 Proleukin 會產生各種 IL-2 活性的免疫標誌物，其中大部分是有毒的，但它也可以在少數患者中治愈它們。所以我認為這就是我們所擁有的。而且我認為我們如何定位自己真的很強大。我會說參考最近的一些 REZPEG 新聞，我會說狼瘡是許多成功藥物在真菌試驗中失敗的領域，這是一個具有挑戰性的發展空間。當然，Xencor 過去在狼瘡的 II 期數據中有過一些棘手的矛盾數據。因此，我們將深入研究這一點，但我會說，這對狼瘡 II 期真的是一個艱難的通讀。

And Bassil, if I can, I'll just follow up on that question about the interferon gamma. So the reason interferon gamma is so important is it does a couple of things. First and foremost, it can have a direct tumoricidal effect where probably more intriguingly is the most famous thing it does. It does 2 famous things to tumor cells. It up-regulates Class I MHC, and that's what the T cell receptors are looking for to recognize the tumor cells. So that's a really desirable activity. And then the other famous thing it does is up-regulate PD-L1, and that's exactly why combining an IL-12 with pembrolizumab or other checkpoint inhibitor makes a lot of sense.

Bassil，如果可以的話，我會跟進有關干擾素伽馬的問題。所以乾擾素 γ 之所以如此重要，是因為它可以做幾件事。首先，它可以具有直接的腫瘤殺滅作用，而更有趣的是它所做的最著名的事情。它對腫瘤細胞做了 2 件著名的事情。它上調 I 類 MHC，這就是 T 細胞受體正在尋找的識別腫瘤細胞的東西。所以這是一個非常理想的活動。然後它做的另一件著名的事情是上調 PD-L1，這就是為什麼將 IL-12 與 pembrolizumab 或其他檢查點抑製劑結合使用很有意義。

Can I ask you why did you guys choose to develop an IL-2 agonist first as opposed to, I think, going to autoimmune direction rather than oncology?

我能問你們為什麼你們首先選擇開發 IL-2 激動劑而不是，我認為，去自身免疫方向而不是腫瘤學嗎？

Well, we think that, that was a great hypothesis and we already -- to try Treg boosting for autoimmune, and we already have our IL-15, which addresses much the same pathway that we think was a better-suited natural precursor molecule for our engineering. So it would have been redundant to do an IL-2 given XmAb306 and the really promising Phase I data we've seen with it so far.

好吧，我們認為，這是一個很好的假設，我們已經——嘗試通過 Treg 促進自身免疫，我們已經有了 IL-15，它解決了與我們認為更適合的天然前體分子相同的途徑我們的工程。因此，鑑於 XmAb306 和我們迄今為止看到的真正有前途的 I 期數據，做 IL-2 是多餘的。

Our next question will come from Brian Cheng of JPMorgan.

我們的下一個問題將來自摩根大通的 Brian Cheng。

Just going back to vudalimab, we're curious if there's any strategic shift in your way of thinking around the development of vudalimab. And Astra is planning to start Phase III with their own bispecific later this year. And I have a follow-up.

回到 vudalimab，我們很好奇您圍繞 vudalimab 開發的思維方式是否有任何戰略轉變。 Astra 計劃在今年晚些時候用他們自己的雙特異性藥物啟動 III 期。我有一個後續行動。

Yes, we're certainly aware of that data from Astra and think that it's very promising. We know that our molecule XmAb -- I forgot, it's called XmAb717, vudalimab shares a very similar design, monomer binding to both targets, essentially very limited CTLA-4 binding without PDL -- PD-1 binding, so it's very conditional binding. And so we think that's a really interesting comparison set.

是的，我們當然知道來自 Astra 的數據，並認為它非常有前途。我們知道我們的分子 XmAb——我忘記了，它叫做 XmAb717，vudalimab 具有非常相似的設計，單體結合兩個目標，基本上非常有限的 CTLA-4 結合沒有 PDL——PD-1 結合，所以它是非常有條件的結合。所以我們認為這是一個非常有趣的比較集。

We're looking very hard at that. We're thinking through possible game plans and hope to be able to guide on that really soon. So yes, it's a very relevant point. And I think the key element there is their willingness to combine with highly active chemo regimens in frontline lung where you really, I think, have to have chemo as part of your backbone given that the comparator is a chemo PD-1 combo.

我們正在非常努力地研究這一點。我們正在考慮可能的遊戲計劃，並希望能夠很快就此提供指導。所以是的，這是一個非常相關的觀點。我認為關鍵因素是他們願意在前線肺部與高度活躍的化療方案相結合，我認為，考慮到比較藥物是化療 PD-1 組合，你真的必須將化療作為你的骨幹的一部分。

I think that that's a really intriguing synergy with our thinking around using aggressive chemo and prostate cancer and some of the experience we gained there. So more to talk about that later, but it's something which is definitely on our radar.

我認為這與我們圍繞使用侵襲性化療和前列腺癌的想法以及我們在那裡獲得的一些經驗形成了非常有趣的協同作用。所以稍後再談這個，但這絕對是我們關注的事情。

Great. And just related to 662, are there any learnings from either interleukin approaches in the past that give you a better sense of what's the low-hanging fruit here for 662 in terms of the solid tumor type that you think could be most sensitive to the IL-12 approach?

偉大的。僅與 662 相關，是否有任何從過去的白細胞介素方法中學到的東西可以讓您更好地了解 662 就您認為可能對 IL 最敏感的實體瘤類型而言容易實現的成果是什麼-12方法？

John, do you want to tackle that one?

約翰，你想解決那個問題嗎？

Yes. I mean I would build off of my response a second ago about we expect 662 to submit a lot of interferon gamma, up-regulate Class I MHC. And so probably the low-hanging fruit, as you put it, would be to go after the more immunogenic tumor types like melanoma, places where checkpoint inhibitors have already worked. There's, of course, certain practical synergies with that approach as well.

是的。我的意思是，我會在一秒鐘前建立我的回應，我們預計 662 會提交大量干擾素伽瑪，上調 I 類 MHC。因此，正如您所說，輕而易舉的成果可能是針對更具免疫原性的腫瘤類型，如黑色素瘤，檢查點抑製劑已經在這些地方發揮作用。當然，這種方法也有一定的實際協同作用。

But maybe the slightly higher hanging fruit would be to go after histologies that have struggled a little bit, shown simple signs, a little bit of evidence of activity with checkpoint inhibitor so that if we can make those tumors more immunogenic with an IL-12, then that's a whole new opportunity space.

但也許稍微高一點的懸而未決的果實是追求有點掙扎的組織學，顯示出簡單的跡象，檢查點抑製劑有一點活性證據，這樣如果我們可以用 IL-12 使這些腫瘤更具免疫原性，那麼這是一個全新的機會空間。

Great. Good luck on the move.

偉大的。祝你好運。

Our next question will come from the line of Peter Lawson of Barclays.

我們的下一個問題將來自巴克萊銀行的彼得勞森。

This is [Shale] for Peter. We were hoping to get an update around your ENPP3 program, 819, and how the progress is there, how we should be thinking about timing for initial data and for the recommended Phase II dose, whether that might be something we see in 2023...

這是 Peter 的 [Shale]。我們希望了解您的 ENPP3 計劃 819 的最新情況，以及進展如何，我們應該如何考慮初始數據的時間安排和推薦的 II 期劑量，這是否可能是我們在 2023 年看到的。 .

We could just barely hear you just from a volume perspective, if you could speak up, we know you're asking about 819.

我們幾乎無法從音量角度聽到您的聲音，如果您能大聲說出來，我們知道您在詢問 819。

Apologies. Is it better now?

道歉。現在好點了嗎？

Yes, that is.

對，是。

Okay, perfect. We were just hoping to get an update on your 819 program for the ENPP3. And just how progress is going there? And if we could see initial data and maybe recommend a Phase II dose in 2023? And then just secondly, how we should be thinking about how this will compare profile-wise to Astellas' ENPP3 ADC program? Any color there would be great.

好的，完美。我們只是希望獲得有關 ENPP3 的 819 程序的更新。進展如何？如果我們能看到初始數據並可能在 2023 年推薦 II 期劑量？其次，我們應該如何考慮這將如何與 Astellas 的 ENPP3 ADC 程序進行比較？任何顏色都會很棒。

So I guess on the update, it's -- we're about 6 months in or 7 months into the Phase I dose escalation. And I think one thing we'll say is that investigators in renal cell carcinoma are very enthusiastic to have the option of a CD3 and therefore are -- have been great collaborators, and we've been recruiting patients really well.

所以我想在更新時，它是 - 我們進入 I 期劑量升級大約 6 個月或 7 個月。我想我們要說的一件事是，腎細胞癌的研究人員非常熱衷於選擇 CD3，因此 - 一直是很好的合作者，我們一直在很好地招募患者。

So I think that's all we can say about that yet. We don't have a timing on data guidance, and we'll do that as we advance in cohorts and understand better the regimen when we would guide on how we're seeing those. We're not giving a timing update on that yet, other than saying the accrual has been going really, really well.

所以我認為這就是我們所能說的。我們沒有數據指導的時間安排，當我們指導我們如何看待這些時，我們會在隊列中推進並更好地理解方案時這樣做。我們還沒有給出時間更新，只是說應計收益一直非常非常好。

The profile of a CD3 versus -- a particular 2+1 CD3 versus an ADC, we hope would have a completely different kind of side effect profile that offers something that physicians don't have right now compared to salvage chemo.

CD3 與 - 特定 2+1 CD3 與 ADC 的對比，我們希望有一種完全不同的副作用曲線，提供醫生目前與挽救化療相比所沒有的東西。

I mean any comments there, Allen, in that particular space?

我的意思是，艾倫，在那個特定的空間裡有什麼評論嗎？

Yes. Renal cancer has been one of those tumors that are traditionally immuno-responsive. And so we think that the immunotherapy would hopefully have an advantage. But it's still early days. And as Bassil said, we have high investigator interest. They're really hungry for this MOA and this disease type. And so we're very excited.

是的。腎癌一直是傳統上具有免疫反應的腫瘤之一。因此，我們認為免疫療法有望取得優勢。但現在還為時尚早。正如 Bassil 所說，我們有很高的調查興趣。他們真的很渴望這種恐鳥和這種疾病。所以我們非常興奮。

I also will add, we can't sort of predict what our recommended Phase II dose will be and how many cohorts we need to get there. But along with investigator interest, the trial design is fairly novel in terms of how we're escalating without disclosing our strategy there that allows us to sort of aggressively pursue the recommended Phase II dose, both in the priming dose and the actual step-up dosing as well as the final highest dose as well.

我還要補充一點，我們無法預測我們推薦的 II 期劑量是多少，以及我們需要多少隊列才能到達那裡。但隨著研究者的興趣，試驗設計在我們如何升級而不公開我們的策略方面是相當新穎的，這使我們能夠在某種程度上積極追求推薦的 II 期劑量，包括啟動劑量和實際遞增劑量劑量以及最終的最高劑量也是如此。

And our next question will come from Gregory Renza of RBC Capital Markets.

我們的下一個問題將來自 RBC Capital Markets 的 Gregory Renza。

It's [Anish] on for Greg. Congrats on the progress. Just on the XmAb 2+1 design for 819 and AMG 509, being armed with the knowledge of these compounds, what's the ultimate effect on the development and future of the 1+1 class, so the future of plamotamab and 968?

格雷格的 [Anish] 上場了。祝賀進步。就 819 和 AMG 509 的 XmAb 2+1 設計而言，掌握這些化合物的知識，對 1+1 類的發展和未來的最終影響是什麼，那麼 plamotamab 和 968 的未來是什麼？

I'll let John handle that and give a thoughtful response. But I will just tell you, 1+1 has plenty of roles to play if you know how to pick properly. John?

我會讓 John 處理這件事並給出深思熟慮的回應。但我只想告訴你，如果你知道如何正確選擇，1+1 可以發揮很多作用。約翰？

Yes. Yes, I think the easiest way to think about that is 1+1 worked really well for plamotamab because it's very well established. You can get rid of all your B cells and hopefully, including the lymphoma B cells. And that's an on-target, off-tumor toxicity that is -- it's fine to live with that.

是的。是的，我認為最簡單的思考方式是 1+1 對 plamotamab 非常有效，因為它已經非常成熟。你可以擺脫所有的 B 細胞，希望包括淋巴瘤 B 細胞。這是一種中靶、脫瘤毒性——可以接受。

When you go into the solid tumor setting, you've got to be a little more careful. And a lot depends on the target and the selectivity profile of the target. How well it's over-expressed and selectively expressed in the tumor versus normal tissue also would depend to some extent on which of the normal tissue it's expressed in because some are a little bit more dangerous to attack than others.

當你進入實體瘤環境時，你必須更加小心。很大程度上取決於目標和目標的選擇性分佈。與正常組織相比，它在腫瘤中過度表達和選擇性表達的程度在某種程度上也取決於它在哪個正常組織中表達，因為有些組織比其他組織更容易受到攻擊。

So in general, we don't see a downside to using the 2+1. And so we'll likely use that for most of our solid tumor targets, but there could be exceptions.

所以總的來說，我們看不到使用 2+1 的缺點。因此，我們可能會將其用於我們的大多數實體瘤目標，但也可能有例外。

Our next question will come from the line of Jonathan Chang of SVB Securities.

我們的下一個問題將來自 SVB 證券的 Jonathan Chang。

This is Matt Cowper on for Jonathan Chang. I know you said that the PSMA CD28 data, we're validating the class kind of broadly. But looking at the data, it didn't have like the cleanest AE profile, particularly with regards to the immune-mediated responses. So just kind of wanted to get your thoughts on how you're thinking about the AE profile for this class sort of in light of what we've seen with CD28 monotherapy approaches and then sort of maybe discuss how your approach might mitigate some of these effects.

這是 Jonathan Chang 的 Matt Cowper。我知道你說過 PSMA CD28 數據，我們正在廣泛地驗證類。但從數據來看，它並沒有最乾淨的 AE 概況，尤其是在免疫介導的反應方面。所以只是想根據我們在 CD28 單一療法方法中看到的情況，了解您如何考慮此類的 AE 概況，然後可能會討論您的方法如何減輕其中的一些效果。

Yes. I think that the choice of co-target, we believe, is going to be very important. It was interesting that some of the AEs, the most dangerous AEs that we're seeing are ones that are not typical for a PD-1 inhibitor. Well, look, remember, that study was done combining it with the PD-1 inhibitor cemiplimab. And you saw, in particular, central nervous system involvement in a couple of patients, peripheral nerve involvement in a couple of patients or in one patient. And it's notable that the target choice, PSMA, outside of prostate, has among its brightest expression in brain and nerve.

是的。我認為，我們相信共同目標的選擇將非常重要。有趣的是，一些 AE，我們看到的最危險的 AE 是 PD-1 抑製劑不常見的。好吧，記住，那項研究是將它與 PD-1 抑製劑 cemiplimab 結合完成的。你看到，特別是幾個病人的中樞神經系統受累，幾個病人或一個病人的周圍神經受累。值得注意的是，前列腺以外的目標選擇 PSMA 在大腦和神經中表現最為突出。

So I think there is a quite reasonable hypothesis there that you're activating immune response against the target and the tissues that have that target. And in fact, I think the sponsor of the study emphasized that they saw those AEs in patients that responded. Very early data and it's hard to make too much of it, but I think that the idea that CD28 can greatly activate the immune system in cold tumors has been pretty convincingly demonstrated. Now the question is can, by prudent choice of target, we make a great drug? We're exploring that, but we're excited about the prospect.

所以我認為有一個非常合理的假設，即你正在激活針對目標和具有該目標的組織的免疫反應。事實上，我認為該研究的發起人強調他們在有反應的患者中看到了那些 AE。非常早期的數據，很難對它做出太多，但我認為 CD28 可以極大地激活寒冷腫瘤中的免疫系統的想法已經得到了非常有說服力的證明。現在的問題是，通過審慎選擇目標，我們能否製造出出色的藥物？我們正在探索這一點，但我們對前景感到興奮。

I see no further questions in the queue. I would now like to turn the conference back to Bassil Dahiyat for closing remarks.

我看隊列中沒有其他問題。我現在想把會議轉回 Bassil Dahiyat 作閉幕詞。

Thanks, everyone, for joining us today, and we look forward to updating you throughout the year. Have a great evening.

感謝大家今天加入我們，我們期待著全年為您更新。祝你有個愉快的夜晚。

This concludes today's conference call. Thank you all for participating. You may now disconnect, and have a pleasant day.

今天的電話會議到此結束。謝謝大家的參與。您現在可以斷開連接，並度過愉快的一天。