Bolt Biotherapeutics Inc (BOLT) 2024 Q1 法說會逐字稿

Good afternoon and welcome to the Bolt Biotherapeutics strategic update conference call. (Operator Instructions) As a reminder, this call may be recorded.

下午好，歡迎參加 Bolt Biotherapeutics 策略更新電話會議。（操作員說明）謹此提醒，此通話可能會被錄音。

I would now like to hand the call over to Willie Quinn, incoming Chief Executive Officer of Bolt Biotherapeutics. Please go ahead, sir.

我現在想將電話交給博爾特生物治療公司即將上任的執行長威利·奎恩 (Willie Quinn)。請繼續，先生。

Thank you, and good afternoon, everyone. This afternoon, we issued our first-quarter 2024 financial results and business update, which outlines the topics we plan to discuss today. You can access the press release by going to the Investors and Media section of our website at www.boltbio.com.

謝謝大家，大家下午好。今天下午，我們發布了 2024 年第一季財務業績和業務更新，其中概述了我們今天計劃討論的主題。您可以造訪我們網站 www.boltbio.com 的投資者和媒體部分以取得新聞稿。

I am joined today by Randy Schatzman, outgoing Chief Executive Officer; and Edith Perez, outgoing Chief Medical Officer. I am also joined by some newly promoted members of Bolt's senior leadership team, including Michael Alonso, Co-Founder of Bolt and newly promoted Senior Vice President of Research; and Dawn Colburn, newly promoted Senior Vice President of Clinical Development.

今天，即將離任的執行長蘭迪·沙茨曼 (Randy Schatzman) 也加入了我的行列。以及即將離任的首席醫療官伊迪絲·佩雷斯 (Edith Perez)。與我一起加入的還有博爾特高級領導團隊的一些新晉升成員，包括博爾特聯合創始人、新晉升的研究高級副總裁邁克爾·阿隆索；以及新晉升的臨床開發資深副總裁 Dawn Colburn。

Before we begin, I'd like to remind everyone that during this call, we will be making forward-looking statements that are subject to a number of risks and uncertainties. These may cause our actual results to differ materially, and I encourage you to read our SEC filings for more details on these risks and uncertainties. You are cautioned not to place any undue reliance on these forward-looking statements and Bolt disclaims any obligations to update such statements.

在開始之前，我想提醒大家，在這次電話會議中，我們將做出前瞻性聲明，這些聲明會受到許多風險和不確定性的影響。這些可能會導致我們的實際結果出現重大差異，我鼓勵您閱讀我們向 SEC 提交的文件，以了解有關這些風險和不確定性的更多詳細資訊。請您注意不要過度依賴這些前瞻性陳述，博爾特不承擔任何更新此類陳述的義務。

To start, I'd like to thank everyone for joining us today. As you all know, we don't normally have earnings calls, but we decided it would be a good idea to have a call today to clearly communicate our new vision for Bolt.

首先，我要感謝大家今天加入我們。眾所周知，我們通常不會召開財報電話會議，但我們認為今天召開電話會議以清楚地傳達我們對博爾特的新願景是個好主意。

On today's call, we will provide details regarding strategic pipeline and leadership changes as well as reviewing our progress during the first quarter. We believe these strategic changes will enable us to optimize the company's operations, maximize shareholder value, and most importantly, deliver meaningful benefit to the many patients with cancer who could benefit from more effective treatment options.

在今天的電話會議上，我們將提供有關策略管道和領導層變動的詳細信息，並回顧第一季度的進展。我們相信這些策略變化將使我們能夠優化公司運營，最大化股東價值，最重要的是，為許多可以從更有效的治療方案中受益的癌症患者帶來有意義的利益。

I'd like to start the call by addressing our decision to discontinue development of BDC-1001. And for that, I'd like to call on my colleague, Dr. Edith Perez. As one of the foremost experts on HER2-positive breast cancer, Edith helped us navigate this landscape and recruit a stellar group of investigators. Edith?

我想先討論我們停止開發 BDC-1001 的決定。為此，我想請教我的同事伊迪絲·佩雷斯博士。身為 HER2 陽性乳癌領域最重要的專家之一，Edith 幫助我們駕馭這一領域並招募了一群優秀的研究人員。伊迪絲？

Thank you, Willie. I am proud of the work that we've done to establish that our role to body immune stimulating antibody conjugates or Boltbody ISAC can be seen today delivered and can produce anti-tumor activity in patients with metastatic solid malignancies.

謝謝你，威利。我為我們所做的工作感到自豪，我們的身體免疫刺激抗體綴合物或 Boltbody ISAC 的作用今天可以看到，並且可以在轉移性實體惡性腫瘤患者中產生抗腫瘤活性。

I am grateful for the collaboration with world-leading investigators who understood and understand the promise of the ISAC approach, and I want to thank them and their patients for all they have done to help advance the scientific understanding of how these brand-new platform of ISACs may ultimately improve cancer care. We continue to build upon that foundation with our next-generation ISAC programs.

我很感謝與世界領先的研究人員的合作，他們理解並了解 ISAC 方法的前景，我要感謝他們和他們的患者為幫助推進對這些全新平台如何進行科學理解所做的一切。癌症護理。我們將繼續在此基礎上推出下一代 ISAC 計劃。

We have decided to discontinue all development of BDC-1001, and we'll work with our investigators to achieve an orderly shutdown of our trials. Deciding to discontinue a program is never easy, especially when one sees signs of activity and evidence supporting our proposed mechanism of action.

我們已決定停止 BDC-1001 的所有開發，我們將與研究人員合作，有序關閉我們的試驗。決定停止一項計劃從來都不是一件容易的事，尤其是當人們看到支持我們提議的行動機制的活動跡象和證據時。

However, we have limited resources and most focused resources on our product conjugate that have the highest potential. We set out to reproduce a 30% overall response rate that we saw in BDC-1001 dose escalation trial.

然而，我們的資源有限，最集中的資源是我們最有潛力的產品結合物。我們著手重現 BDC-1001 劑量遞增試驗中 30% 的整體緩解率。

We did not see that in the Phase 2 portion of the program. However, the clinical activity of BDC-1001 along with significant advances in our next-generation ISAC technology have encouraged us to shift resources to our Claudin 18.2 targeting next-generation ISAC program and our ongoing Phase 1 study of our Dectin-2 agonist antibody.

我們在該計劃的第二階段部分沒有看到這一點。然而，BDC-1001 的臨床活動以及我們下一代 ISAC 技術的重大進步鼓勵我們將資源轉移到針對下一代 ISAC 計劃的 Claudin 18.2 項目以及我們正在進行的 Dectin-2 激動劑抗體的 1 期研究。

With these changes, I have decided to transition to an advisory role and hand over the reins to Dawn Colburn, who is being promoted to Senior Vice President of Clinical Development. Dawn joined Bolt in 2023, bringing over two decades of experience in oncology and clinical development. Prior to joining Bolt, she was Vice President of Clinical Science at Agenus and Arcus Biosciences, where she built and led the clinical science organization and the non-small cell lung cancer development strategy of both organizations.

隨著這些變化，我決定過渡到顧問角色，並將領導權移交給道恩·科爾伯恩 (Dawn Colburn)，他將晉升為臨床開發高級副總裁。Dawn 於 2023 年加入 Bolt，帶來了二十多年的腫瘤學和臨床開發經驗。在加入 Bolt 之前，她曾擔任 Agenus 和 Arcus Biosciences 的臨床科學副總裁，建立並領導了兩個組織的臨床科學組織和非小細胞肺癌開發策略。

I am happy that Bolt's clinical progress are in good hands, and I look forward to continuing to work with Dawn and the team in an advisory role. And with that, I'll now hand over the call to Randy. Randy?

我很高興 Bolt 的臨床進展得到了很好的照顧，我期待繼續與 Dawn 和團隊合作，擔任顧問角色。現在我將把電話轉給蘭迪。蘭迪？

Thank you, Edith. Bolt will now be shifting away from BDC-1001 and prioritizing BDC-3042 and BDC-4182, our next-gen ISAC-targeting Claudin 18.2, which incorporates five years of advancement in ISAC design parameters. In conjunction with the strategic refocusing, the company will be reducing its workforce by approximately 50%.

謝謝你，伊迪絲。Bolt 現在將放棄 BDC-1001，優先考慮 BDC-3042 和 BDC-4182，這是我們的下一代 ISAC 目標 Claudin 18.2，它融合了 ISAC 設計參數五年來的進步。結合策略調整，該公司將裁員約 50%。

As a result of these actions, we expect to extend our cash runway into the second half of 2026, which enables us to achieve clinical data on our next-generation ISAC and our Dectin-2 program with our existing resources.

透過這些行動，我們預計將現金跑道延長至 2026 年下半年，這使我們能夠利用現有資源獲得下一代 ISAC 和 Dectin-2 計畫的臨床數據。

As part of this refocusing, we've also made leadership changes that will best serve the company's path moving forward. My colleague, Willie Quinn, Bolt's long-standing Chief Financial Officer, will be stepping in as Chief Executive Officer.

作為重新調整重點的一部分，我們也進行了領導層變動，以最好地服務公司的前進道路。我的同事、博爾​​特長期擔任的財務長威利·奎恩 (Willie Quinn) 將接任執行長一職。

Willie has been a strong leader at Bolt since joining the company four years ago with expertise in executing operational and financial strategies, driving corporate growth, and raising capital. He has been an invaluable partner to myself and to Bolt's Board of Directors in overseeing all aspects of the company.

自四年前加入 Bolt 以來，Willie 一直是 Bolt 的強有力的領導者，在執行營運和財務策略、推動公司發展和籌集資金方面擁有專業知識。在監督公司的各個方面，他一直是我本人和博爾特董事會的寶貴合作夥伴。

We anticipate a seamless transition, and I look forward to transitioning into a strategic advisory role in continuing to be involved in that capacity. Along with these changes, we're also reducing the size of Bolt's Board by two directors. Bolt's Founder, Ed Engleman, is stepping down from the Board of Directors and into a position on our Scientific Advisory Committee. Dr. Engleman founded the company in 2015 to expand on its pioneering work in cancer and immuno therapeutics and myeloid biology conducted at Stanford University. We're glad that he will be able to continue to be a resource for us here at Bolt.

我們預計會實現無縫過渡，我期待著轉變為策略顧問角色，並繼續參與這一職位。除了這些變化之外，我們還減少了博爾特董事會的規模，減少了兩名董事。Bolt 的創辦人 Ed Engleman 將從董事會辭職，轉而擔任我們的科學諮詢委員會成員。Engleman 博士於 2015 年創立了該公司，以擴大其在史丹佛大學進行的癌症和免疫治療以及骨髓生物學方面的開創性工作。我們很高興他能夠繼續成為我們博爾特的資源。

Dr. Richard Miller has also decided to not stand for reelection when his term expires in June. Dr. Miller has served on our Board since 2017, and we are grateful for his drug development perspective over the years.

理查德·米勒博士也決定在六月任期屆滿時不再競選連任。Miller 博士自 2017 年以來一直在我們的董事會任職，我們感謝他多年來對藥物開發的看法。

Finally, I want to thank all the dedicated and talented employees who will be leaving as part of this realignment. It's been a true pleasure to work with you for these past five years.

最後，我要感謝所有將在此次重組中離職的敬業且才華橫溢的員工。在過去的五年裡與您一起工作真的很愉快。

With that, I'd like to pass the call back to Bolt's incoming Chief Executive Officer, Willie Quinn, to provide an overview of the company's strategy and platform. Willie?

至此，我想將電話轉給博爾特即將上任的執行長威利·奎恩 (Willie Quinn)，以概述公司的策略和平台。威利？

Thank you, Randy. Before I start, I want to thank all Bolt's employees, and particularly, Randy, Edith, Ed, and Richard for their leadership and advancing the company to where we are today. While our priorities are shifting, our mission remains the same to leverage the power of the immune system to find better ways to treat cancer.

謝謝你，蘭迪。在開始之前，我要感謝博爾特的所有員工，特別是蘭迪、伊迪絲、艾德和理查德，感謝他們的領導和推動公司取得今天的成就。雖然我們的優先事項正在發生變化，但我們的使命仍然相同，即利用免疫系統的力量來尋找更好的癌症治療方法。

This is not an easy path and drug development is inherently risky, but we are making progress. Our understanding of the relation between the immune system and tumor microenvironment continues to improve and our ISAC platform is dramatically better than it was only a few years ago.

這不是一條容易的道路，藥物開發本身就存在風險，但我們正在取得進展。我們對免疫系統和腫瘤微環境之間關係的理解不斷提高，我們的 ISAC 平台比幾年前好得多。

As a reminder, at Bolt, we are developing product candidates with the goal of training a patient's own immune system to recognize and eliminate their cancer. We do this by focusing on the tumor microenvironment which almost always contains some myeloid cells.

提醒一下，在 Bolt，我們正在開發候選產品，目的是訓練患者自身的免疫系統來識別和消除癌症。我們透過專注於幾乎總是包含一些骨髓細胞的腫瘤微環境來做到這一點。

Myeloid cells such as macrophages and dendritic cells are part of what is called the innate immune system. Their function is to recognize molecular patterns unique to pathogens such as bacteria, fungi, and viruses. Our product candidates find ways to use this system to train the body to mount an immune response targeted at the cancer.

巨噬細胞和樹突狀細胞等骨髓細胞是先天免疫系統的一部分。它們的功能是識別細菌、真菌和病毒等病原體特有的分子模式。我們的候選產品找到了使用該系統來訓練身體針對癌症發起免疫反應的方法。

We have three clear priorities going forward: BDC-3042, BDC-4182, and our collaborations. We believe BDC-3042, our first-in-class agonist antibody that reawakens myeloid cells so they can attack tumor cells has broad application across many tumor types. And we are encouraged that BDC-3042 seems safe and well tolerated in the Phase 1 dose escalation thus far.

我們未來有三個明確的優先事項：BDC-3042、BDC-4182 和我們的合作。我們相信 BDC-3042 是我們的一流激動劑抗體，可重新喚醒骨髓細胞，使其能夠攻擊腫瘤細胞，在許多腫瘤類型中具有廣泛的應用。我們感到鼓舞的是，迄今為止，BDC-3042 在 1 期劑量遞增中似乎是安全的且耐受性良好。

In today's call, you will also hear more about BDC-4182, the first next-generation Boltbody ISAC to advance into IND-enabling studies. BDC-4182 targets Claudin 18.2 and has very promising preclinical data.

在今天的電話會議中，您還將聽到有關 BDC-4182 的更多信息，這是第一個進入 IND 支援研究的下一代 Boltbody ISAC。BDC-4182 針對 Claudin 18.2，並且有非常有希望的臨床前數據。

Finally, we are committed to supporting our collaboration partners, Genmab and Toray, and look forward to providing details on some of those exciting programs later this year.

最後，我們致力於支持我們的合作夥伴 Genmab 和東麗，並期待在今年稍後提供一些令人興奮的項目的詳細資訊。

With that, I would like to turn the call over to Dawn Colburn, our Senior Vice President of Clinical Development to discuss BDC-3042 in greater detail.

因此，我想將電話轉給我們的臨床開發高級副總裁 Dawn Colburn，以更詳細地討論 BDC-3042。

Thank you, Willie. Turning now to BDC-3042, BDC-3042 is a first-in-class Decton-2 agonist monoclonal antibody that reprograms tumor-associated macrophages to attack tumor cells. Dectin-2 gene expression is elevated in tumor-associated macrophages across a broad range of solid tumor types.

謝謝你，威利。現在轉向 BDC-3042，BDC-3042 是一流的 Decton-2 激動劑單株抗體，可重新編程腫瘤相關巨噬細胞以攻擊腫瘤細胞。Dectin-2 基因表現在多種實體腫瘤類型的腫瘤相關巨噬細胞中升高。

The ongoing first-in-human clinical study is currently evaluating BDC-3042 in patients with six types of metastatic or unresectable cancer, including triple-negative breast cancer, colorectal cancer, clear cell renal cell carcinoma, head and neck cancer, non-small cell lung cancer, and ovarian cancer.

正在進行的首次人體臨床研究目前正在評估BDC-3042 在六種類型的轉移性或不可切除癌症患者中的作用，包括三陰性乳癌、大腸直腸癌、透明細胞腎細胞癌、頭頸癌、非小細胞癌細胞肺癌和卵巢癌。

The study starts with dose escalation of BDC-3042 as a single agent to evaluate the safety and determine the recommended Phase 2 dose. BDC-3042 has advanced through the first three dose escalation cohorts without any dose-limiting toxicities and the fourth dose level cohort is fully enrolled. BDC-3042 has been well tolerated to date. We anticipate providing an update on enrollment and safety in the latter half of this year.

研究從 BDC-3042 作為單一藥物的劑量遞增開始，以評估安全性並確定建議的 2 期劑量。BDC-3042 已通過前三個劑量遞增隊列，沒有任何劑量限制毒性，第四個劑量水平隊列已完全入組。迄今為止，BDC-3042 的耐受性良好。我們預計在今年下半年提供有關入學和安全的最新資訊。

I'd like to now hand it off to Michael Alonso, our Senior Vice President of Research, to provide an overview of BDC-4182.

我現在想將其交給我們的高級研究副總裁 Michael Alonso，他將概述 BDC-4182。

Thank you, Dawn. I'm happy to join the call today to explain why we are so excited about our next-generation Boltbody ISAC platform and about our Claudin 18.2 Boltbody ISAC, in particular. As a reminder, an ISAC is comprised of a tumor-targeting antibody and an immune stimulating payload.

謝謝你，黎明。我很高興參加今天的電話會議，解釋為什麼我們對下一代 Boltbody ISAC 平台，特別是我們的 Claudin 18.2 Boltbody ISAC 如此興奮。提醒一下，ISAC 由腫瘤靶向抗體和免疫刺激有效負載組成。

Over the last several years, we have continued to advance our Boltbody ISAC technology, and they've come to appreciate the importance for the antibody, the [weaker], the payload, and the combination of the three. We have developed next-generation ISAC with enhanced potency and activities that have the potential to deliver superior efficacy with acceptable safety.

在過去的幾年裡，我們不斷推進 Boltbody ISAC 技術，他們已經認識到抗體、[較弱的]、有效負載以及三者組合的重要性。我們開發了具有增強效力和活性的下一代 ISAC，有可能提供卓越的功效和可接受的安全性。

We have generated preclinical data showing that our next-generation Boltbody ISAC can provide better efficacy than naked antibodies and even better than cytotoxic antibody-drug conjugates or ADCs. We have also generated anti-tumor activity in preclinical models with lower antigen density, tumor models where our first-generation ISAC underperformed.

我們產生的臨床前數據表明，我們的下一代 Boltbody ISAC 可以提供比裸抗體更好的功效，甚至比細胞毒性抗體-藥物偶聯物或 ADC 更好。我們也在抗原密度較低的臨床前模型中產生了抗腫瘤活性，而我們的第一代 ISAC 表現不佳的腫瘤模型。

I'll now turn to our exciting new program that we are unveiling today, BDC-4182, which targets Claudin 18.2 Claudin 18.2 is a protein that is expressed in the stomach epithelial, and in healthy cells, it is somewhat hidden in the transmembrane tight junctions. In cancers, such as gastric and pancreatic cancer, expression of Claudin 18.2 is significantly elevated. Claudin 18.2 in these tumor is also localized to surfaces that are more readily accessible to biologic and effector cells, thereby providing an expression pattern and makes for an excellent target for ISAC.

現在我將談談我們今天推出的令人興奮的新計劃，BDC-4182，它針對Claudin 18.2 Claudin 18.2 是一種在胃上皮中表達的蛋白質，在健康細胞中，它在某種程度上隱藏在跨膜緊密中間路口。在胃癌和胰臟癌等癌症中，Claudin 18.2 的表達顯著增加。這些腫瘤中的 Claudin 18.2 也定位於更容易接觸生物細胞和效應細胞的表面，從而提供表達模式並成為 ISAC 的絕佳標靶。

We have incorporated the learnings of BDC-1001 into our next-generation ISAC and designed BDC-4182 with enhanced potency and activity. We are excited by the preclinical data generated to date, indicating that next-generation Claudin 18.2 ISAC has superior anti-tumor activity relative to MMAE-based ADCs and can deliver anti-tumor activity in models with low Claudin 18.2 antigen density.

我們已將 BDC-1001 的經驗融入下一代 ISAC 中，並設計了具有增強效力和活性的 BDC-4182。我們對迄今為止產生的臨床前數據感到興奮，這表明下一代 Claudin 18.2 ISAC 相對於基於 MMAE 的 ADC 具有優異的抗腫瘤活性，並且可以在具有低 Claudin 18.2 抗原密度的模型中提供抗腫瘤活性。

BDC-4182 has advanced to IND-enabling activities supported by preclinical results, demonstrating potent anti-tumor activity, induction of immunological memory with epitope spreading, and importantly, an acceptable safety profile.

BDC-4182 已取得臨床前結果支持的 IND 活性，證明了有效的抗腫瘤活性、透過表位擴散誘導免疫記憶，而且重要的是，具有可接受的安全性。

With that, I'll turn the call back over to Willie for closing remarks. Willie?

之後，我會將電話轉回給威利，讓其結束語。威利？

Thank you, Michael. While it was a difficult decision to pivot away from our first-generation ISAC BDC-1001, we are guided by the strong principle of doing what will ultimately be best for patients. And in this case, that means learning from the data and turning our resources towards our clinical candidate, BDC-3042, and our next-generation ISAC platform.

謝謝你，麥可。雖然放棄第一代 ISAC BDC-1001 是一個艱難的決定，但我們遵循一個堅定的原則：做最終對病人最有利的事情。在這種情況下，這意味著從數據中學習並將我們的資源轉向我們的臨床候選藥物 BDC-3042 和我們的下一代 ISAC 平台。

I'd like to reiterate the excitement we have for our pipeline going forward. We are steadfast in our mission of generating breakthrough immunotherapies for patients with cancer, teaching the innate immune system to recognize and kill multiple tumor types.

我想重申我們對未來管道的興奮。我們堅定不移地致力於為癌症患者提供突破性的免疫療法，教導先天免疫系統識別和殺死多種腫瘤類型。

We have a focused pipeline centered on both proven platform technology as well as improvements that have been further validated by our external collaborations with Genmab and Toray. For our clinical-stage program, BDC-3042, we will plan to share a safety and enrollment update on the Phase 1 dose escalation trial in the second half of this year and we are advancing BDC-4182 towards initiating a clinical trial in 2025.

我們擁有一條以經過驗證的平台技術和改進為中心的重點管道，這些改進已透過我們與 Genmab 和東麗的外部合作得到進一步驗證。對於我們的臨床階段項目 BDC-3042，我們計劃在今年下半年分享 1 期劑量遞增試驗的安全性和入組更新，並且我們正在推進 BDC-4182，爭取在 2025 年啟動臨床試驗。

We have a refreshed and prioritized corporate strategy and are adequately capitalized to achieve our upcoming program milestones into the second half of 2026. Bolt at its core is committed to innovative, groundbreaking science, and I am proud of the progress we have made in advancing such differentiated technology in order to bring positive change to the oncology treatment landscape in the future.

我們制定了更新且優先的企業策略，並擁有充足的資本來實現我們即將在 2026 年下半年實現的計畫里程碑。Bolt 的核心致力於創新、突破性的科學，我為我們在推進這種差異化技術方面取得的進展感到自豪，以便為未來的腫瘤治療領域帶來積極的變化。

We will now open the call up for Q&A, for which we will have available our SVP, Clinical Development, Dawn Colburn; our SVP, Research, Michael Alonso; and myself.

我們現在將開始徵集問答環節，為此我們將邀請臨床開發資深副總裁 Dawn Colburn；我們的研究資深副總裁麥可‧阿隆索；和我自己。

(Operator Instructions) Jeffrey La Rosa, Leerink Partners.

（操作員說明）Jeffrey La Rosa，Leerink Partners。

Hi. Thanks for taking our question today. I'd like to talk more about this -- to ask you more about the Claudin 18.2 ISAC. And can you elaborate more on why and how it is more potent? Then with the first-gen platform, is it just a matter of it being a more potent TLR7/8 agonist? Why are you still confident in TLR7/8 agonist versus other innate stimulants?

你好。感謝您今天提出我們的問題。我想多談談這個問題——向您詢問更多關於 Claudin 18.2 ISAC 的資訊。您能否詳細說明為什麼以及如何它更有效？那麼對於第一代平台來說，它只是一個更有效的 TLR7/8 激動劑嗎？與其他天然興奮劑相比，您為何對 TLR7/8 激動劑仍然充滿信心？

And I guess, part of the HER2 experience with 1001 was really a fierce competitive landscape with high bars with some of the other HER2 mechanisms there. It's pretty similar with Claudin 18.2 with ADCs and T-cell engagers there. How do you think this will play out differently competitively versus HER2 experience? And just kind of talk more about target selection, in general. How that plays into? How you select your new ISAC programs and -- relative to what else is out there? Thank you.

我想，1001 的 HER2 體驗的一部分確實是一個激烈的競爭環境，與其他一些 HER2 機制的門檻很高。它與具有 ADC 和 T 細胞接合器的 Claudin 18.2 非常相似。您認為與 HER2 體驗相比，這在競爭上會有什麼不同？一般來說，多談論目標選擇。這是如何發揮作用的？您如何選擇新的 ISAC 項目以及—相對於其他項目？謝謝。

Yeah, Jeff, those are great questions. This is Willie, and I would like to turn it over to Michael to address those. I think we have some good answers.

是的，傑夫，這些都是很好的問題。我是威利，我想把它交給麥可來解決這些問題。我認為我們有一些很好的答案。

Perfect. Thanks. I think first and foremost, BDC-1001 certainly demonstrates that ISACs can be safely delivered to patients, elicit immune activation in the patient tumors, and produce meaningful clinical benefits. We've taken these learnings and made several design improvements with the next-generation ISACs that lead to enhanced activation of the immune system that we expect will increase the antitumor activity in patients, including those with tumors expressing lower levels of target antigen as we have seen in our preclinical model.

完美的。謝謝。我認為首先也是最重要的是，BDC-1001 無疑證明了 ISAC 可以安全地輸送給患者，在患者腫瘤中引發免疫激活，並產生有意義的臨床益處。我們吸收了這些經驗，並對下一代ISAC 進行了多項設計改進，從而增強了免疫系統的激活，我們預計這將增加患者的抗腫瘤活性，包括那些腫瘤表達較低水平的目標抗原的患者，正如我們所研究的那樣在我們的臨床前模型中看到。

Now, more specifically, as it relates to the ISAC and the design improvements, we've certainly made improvements to the potency of the TLR7 and 8 agonist. We've also made improvements to the antibodies such that we are seeing enhanced phagocytosis and activation of the myeloid cells. And we have an optimization of the conjugation chemistry. And I think by optimizing these features with our common design principles, we've certainly produced ISACs that are much more potent than what we observed with BDC-1001 preclinically and have seen some compelling anti-tumor activity in our preclinical models.

現在，更具體地說，由於它涉及 ISAC 和設計改進，我們當然已經對 TLR7 和 8 激動劑的效力進行了改進。我們也對抗體進行了改進，因此我們看到骨髓細胞的吞噬作用和活化增強。我們對共軛化學進行了優化。我認為，透過使用我們共同的設計原則來優化這些功能，我們確實生產出了比我們在臨床前觀察到的BDC-1001 更有效的ISAC，並且在我們的臨床前模型中看到了一些引人注目的抗腫瘤活性。

As it relates to why TLR7 and 8 versus some of the other immune agonists that are out there, I think from the big-picture standpoint, we still prefer TLR7 and 8 at their end is [optimally] located and can deliver robust activation of the innate immune system and their expression profiles in human nicely covers plasmacytoid dendritic cells as well as monocytes, macrophages, and dendritic cells, which are all cells that when activated can lead to a robust innate immune response that will translate then to be adaptive immune response and get some compelling T-cell immunity.

由於這涉及到為什麼 TLR7 和 8 與其他一些免疫激動劑相比，我認為從大局來看，我們仍然更喜歡 TLR7 和 8 在其末端的[最佳]位置，並且可以提供強有力的激活先天免疫系統及其在人類中的表現譜很好地涵蓋了漿細胞樣樹突狀細胞以及單核細胞、巨噬細胞和樹突狀細胞，這些細胞在被激活時可以導致強大的先天免疫反應，然後轉化為適應性免疫反應和獲得一些引人注目的 T 細胞免疫。

Not to interrupt, but I think the other component that is interesting from a competitive landscape perspective, which is something that we didn't have in the HER2 landscape is [a look] versus cytotoxic ADCs, and maybe you could talk a little bit about that too.

不想打斷，但我認為從競爭格局的角度來看，另一個有趣的組成部分（我們在 HER2 領域沒有）是[看看]與細胞毒性 ADC 的比較，也許你可以談談那也是。

Yeah, so moving into the competitive landscape, we certainly are paying attention to the landscape, notably with what's out there or what's about to be out there with zolbetuximab, a naked antibody, and its activity in patients with high Claudin 18.2 expression, but also what's coming next in some of the early-phase clinical trials. And that's a lot of what we've been seeing is the antibody drug conjugates with the MMA payload.

是的，所以進入競爭格局，我們當然正在關注這一形勢，特別是現有或即將推出的 zolbetuximab（一種裸抗體）及其在 Claudin 18.2 高表達患者中的活性，但也一些早期臨床試驗的下一步是什麼。我們所看到的很多都是抗體藥物與 MMA 有效負載的結合物。

We've taken -- we've made the cytotoxic ADCs in-house and have compare them to the ISACs in syngeneic tumor models with high expression or with medium expression of Claudin 18.25. And we certainly see that the ISACs perform superior to them, at least in our early models that we've assessed to date. So we're certainly positioning ourselves to face the competition and we expect that our differentiated mechanism will provide clinicians with some interesting options as it relates to immune stimulation and the potential for durable immune responses.

我們已經在內部製造了細胞毒性 ADC，並將它們與高表達或中等表達 Claudin 18.25 的同基因腫瘤模型中的 ISAC 進行了比較。我們當然看到 ISAC 的性能優於它們，至少在我們迄今為止評估的早期模型中是如此。因此，我們肯定會做好面對競爭的準備，我們希望我們的差異化機制將為臨床醫生提供一些有趣的選擇，因為它與免疫刺激和持久免疫反應的潛力有關。

And I think your last question was on target selection for the next-generation ISAC, and I'll spend a little bit of time just for Claudin. Right, so why are we interested in Claudin 18.2? I think I touched on that a bit.

我認為你的最後一個問題是關於下一代 ISAC 的目標選擇，我將花一點時間來問克勞丹。是的，那麼我們為什麼對 Claudin 18.2 感興趣呢？我想我已經觸及了一點。

It's certainly been validated now with the experience with zolbetuximab. The expression profile of Claudin 18.2 is also quite compelling. And as much in healthy tissues, it's restricted to the tight junction in the gastric epithelial. And then during tumor genesis or as the cancer progresses, you see it losing some of the cell polarity and then being more readily accessible to biologics.

現在佐爾貝妥昔單抗的經驗肯定已經驗證了這一點。Claudin 18.2 的表達譜也非常引人注目。與健康組織一樣，它僅限於胃上皮的緊密連接。然後在腫瘤發生過程中或隨著癌症的進展，您會看到它失去了一些細胞極性，然後更容易被生物製劑利用。

So we're thinking about the next-generation ISACs that are significantly more potent than the first-generation ISACs while still having safety in mind, very specific expression of the tumor-targeting antigen can certainly lead to a compelling hypothesis to test in the clinic. And that's what we're excited to do.

因此，我們正在考慮下一代 ISAC，它們比第一代 ISAC 更有效，同時仍考慮到安全性，腫瘤靶向抗原的非常特異性的表達肯定會導致令人信服的假設在臨床中進行測試。這就是我們很高興做的事情。

And Jeff, I'll just end by pointing out that we also just uploaded a new corporate presentation, which is available on our website. And it does include a few slides some on the preclinical data that we've generated for BDC-4182. So I encourage you to take a look at that. And obviously, we're happy to have follow-up conversations.

傑夫，我最後要指出的是，我們也剛剛上傳了一份新的公司簡報，可以在我們的網站上找到。它確實包括一些關於我們為 BDC-4182 產生的臨床前數據的幻燈片。所以我鼓勵你看看這個。顯然，我們很高興進行後續對話。

Stephen Willey, Stifel.

史蒂芬威利，斯蒂菲爾。

Yeah, good afternoon. Thanks for taking the question. I guess maybe just a follow up on the prior question and maybe a little bit more specifically, can you talk about the differentiation of the payload on 4182 relative to 1001, I guess, specifically as it pertains to the skew of TLR7 versus 8 agonism? If I remember correctly, I think 1001 was skewed more towards TLR7. Should we assume that and this being more potent to you through that net skew more towards 8?

是的，下午好。感謝您提出問題。我想也許只是前一個問題的後續，也許更具體一點，你能談談 4182 上的有效負載相對於 1001 的區別嗎？如果我沒記錯的話，我認為 1001 更傾向於 TLR7。我們是否應該假設，透過淨偏向 8，這對您來說更有效？

So again, I'll let Michael jump in on that. And I do think we have some good slides that also speak to that. But I'll let him answer the question.

再說一次，我會讓麥可參與其中。我確實認為我們有一些很好的幻燈片也能說明這一點。但我會讓他回答這個問題。

Yeah, I think, aside from getting into how far is it skewed one way or another, I would say that the payload that we're utilizing for BDC-4182 is significantly more potent on both TLR7 and TLR8 relative to what we utilized for BDC-1001.

是的，我認為，除了探討它以某種方式傾斜了多遠之外，我想說的是，相對於我們用於BDC 的負載，我們用於BDC-4182 的有效負載在TLR7 和TLR8 上的效力明顯更強-1001。

And I think what's important and you can reference the corporate deck on slide 21, when you go through these data, is that as you transition from the first-generation linker payload to the second-generation linker payload, our goal is to still activate the innate immune system, which includes the myeloid cells and the plasmacytoid dendritic cells.

我認為重要的是，當您瀏覽這些數據時，您可以參考幻燈片21 上的公司平台，當您從第一代連結器有效負載過渡到第二代連結器有效負載時，我們的目標是仍然活化先天免疫系統，包括骨髓細胞和漿細胞樣樹突細胞。

And what we've learned is that as you climb down the antigen ladder, i.e., if you target tumors with lower antigen density, you see significantly enhanced anti-tumor activity with a next-generation ISAC, not just on Claudin but also on HER2, TROP2, and CEA, relative to the first generation. So we are delivering significantly more activity, be it in-vitro in our preclinical models but also in-vivo in our anti -- in our tumor models.

我們了解到，當您沿著抗原階梯往下爬時，即，如果您針對抗原密度較低的腫瘤，您會發現下一代 ISAC 的抗腫瘤活性顯著增強，不僅針對 Claudin，而且針對 HER2 、TROP2和CEA，相對於第一代。因此，我們正在提供顯著更多的活性，無論是在我們的臨床前模型中的體外，還是在我們的抗腫瘤模型中的體內。

Okay. And then just with respect to 3042, can you just I guess maybe speak to your level of confidence that you'll be able to see monotherapy activity with this agent in dose escalation or even dose expansion? And can you give us any inclination as to what your preclinical data tells you about at what dose level you would expect to maybe see some potential efficacy just based upon the exposures that you're starting to achieve at any given dose level?

好的。然後就 3042 而言，我想您能否談談您對能夠看到該藥物在劑量遞增甚至劑量擴展方面的單一治療活性的信心程度？您能否告訴我們您的臨床前數據告訴您的信息，即根據您在任何給定劑量水平開始達到的暴露量，您期望在什麼劑量水平下可能會看到一些潛在功效？

Thanks, Steve. We are very excited about 3042, and I'll hand it over to Dawn to just talk a little bit about the status of where we are in the clinic there and then either she can talk a little bit about mechanism or Michael can jump in as needed. So Dawn?

謝謝，史蒂夫。我們對 3042 感到非常興奮，我將把它交給 Dawn，讓她簡單談談我們在診所的狀況，然後她可以談談機制，或者 Michael 可以介入。那麼黎明呢？

Yeah, thank you. For a program like 3042, we don't yet know what we will see in the clinic during our dose escalation experience. We are hopeful that we will start seeing some activity at some of the dose levels coming up. It's still very early days and pretty low doses that were administered to these patients.

是的，謝謝。對於像 3042 這樣的項目，我們還不知道在劑量遞增過程中我們會在診所看到什麼。我們希望在某些劑量水平上能夠開始看到一些活動。現在還處於早期階段，對這些患者施用的劑量也相當低。

The preclinical models lead us to believe that we should see monotherapy activity here. And I think it will just need to be borne out in the clinic as to whether or not we will actually see monotherapy activity with this agent. And I'll hand it over to Michael to speak to those expectations.

臨床前模型使我們相信我們應該在這裡看到單一療法的活性。我認為只需要在臨床上證實我們是否真的會看到這種藥物的單一療法活性。我將把它交給邁克爾來表達這些期望。

I think Dawn said it perfectly. I think we are in the range where we are starting to get very interested in the clinical doses and we'll know more as we get to those patients.

我認為黎明說得非常好。我認為我們正處於開始對臨床劑量非常感興趣的範圍內，當我們接觸到這些患者時，我們會了解更多。

Michael Schmidt, Guggenheim.

邁克爾·施密特，古根漢。

Hey, guys. Thanks for taking my question. I had two questions. The first one on BDC-1001. I'm just curious what sort of the trigger was to drop the program. I thought you just had recently initiated the use of expansion cohorts, you know, what's the data from one or more specific cohorts that did not meet the bar? How do we -- and what our learnings from the BDC-1001 experience?

嘿，夥計們。感謝您提出我的問題。我有兩個問題。第一個關於 BDC-1001。我只是好奇是什麼觸發了放棄該程序。我以為您最近才開始使用擴展隊列，您知道，一個或多個未達到標準的特定隊列的資料是什麼？我們如何——以及我們從 BDC-1001 中學到了什麼？

Yeah, great question, Michael. We definitely tried to make this decision as early as we could, in light of the other interesting programs we have, because we wanted to make sure that our precious resources were going in the very best place possible. But it's always a difficult decision, especially when you're seeing signs of clinical activity and you think you might have a program, but you're weighing that against the competitive landscape and what else you could do.

是的，很好的問題，麥可。鑑於我們擁有的其他有趣的計劃，我們確實嘗試儘早做出這個決定，因為我們希望確保我們寶貴的資源盡可能用於最好的地方。但這始終是一個艱難的決定，尤其是當您看到臨床活動的跡象並且您認為自己可能有一個計劃，但您正在權衡競爭格局以及您還可以做什麼時。

And maybe I'll just hand it over to Dawn a little bit, who is a lot closer to the BDC-1001 program and the nitty gritty, and we're not necessarily going to get patient-by-patient details, but I think she can give you a better sense of where we were and how we came to that decision.

也許我會把它交給 Dawn 一點，他更接近 BDC-1001 計劃和實質內容，我們不一定會獲得每個患者的詳細信息，但我認為她可以讓您更好地了解我們的處境以及我們如何做出這個決定。

Certainly. Just to remind, folks, when we set out to do the expansion cohort, what we were trying to do is actually reproduce the data that we saw in our dose-escalation portion of the first BDC -001 clinical trial, and that produced a 29% or 30% overall response rate in a mixed group of heavily pretreated patients.

當然。只是提醒各位，當我們開始進行擴展隊列時，我們試圖做的實際上是重現我們在第一個 BDC -001 臨床試驗的劑量遞增部分中看到的數據，這產生了 29在接受過大量治療的混合患者組中，整體緩解率為% 或30%。

So we opened expansion cohorts with a bar of 30%. And quite frankly, we didn't see that in some of the initial cohorts. And so that's why we took the tough decision to go ahead and discontinue the program at this time to give us the runway to look at these other assets that we have.

因此，我們以 30% 的標準開設了擴展隊列。坦白說，我們在一些最初的群體中沒有看到這一點。因此，我們做出了艱難的決定，繼續並終止該計劃，以便我們有機會審視我們擁有的其他資產。

We still continue to believe very strongly in our ISAC technology. And just to remind, folks, we do -- we have seen interesting biomarker data and clinical activity from the dose escalation. It was very safe and well tolerated. And we will be actually publishing the totality of our dose escalation data in combination with a lot of this biomarker data in an upcoming manuscript.

我們仍然對我們的 ISAC 技術充滿信心。只是提醒一下，各位，我們確實看到了有趣的生物標記數據和劑量遞增的臨床活動。它非常安全且耐受性良好。實際上，我們將在即將發布的手稿中結合大量生物標記數據發布劑量遞增數據的全部內容。

Okay. And on 3042 targeting TAMs, I guess what is the most compelling argument for targeting Dectin-2 and are there any other examples out there of therapies targeting TAMs that could help to de-risk this mechanism, clinically? Thanks.

好的。關於 3042 標靶 TAM，我想針對 Dectin-2 最有說服力的論點是什麼？ 還有其他針對 TAM 的療法的例子可以幫助降低這種機制的臨床風險嗎？謝謝。

Yeah, great. Great question. And we love talking about BDC-3042 because we do think we have a unique first-in-class mechanism. I'm going to hand it over to Michael to talk a little bit more about that target and our decision to go there.

是的，太棒了。很好的問題。我們喜歡談論 BDC-3042，因為我們確實認為我們擁有獨特的一流機制。我將把它交給邁克爾，讓他更多地談論這個目標以及我們實現這一目標的決定。

Yes, perfect. Thanks, Willie. I think for targeting Dectin-2, it's got a couple of things going for it. One is the pattern recognition receptor that when agonized can weak polarized some of the tumor-supported macrophages and convert them into the tumor-destructive macrophages.

是的，完美。謝謝，威利。我認為針對 Dectin-2，它有幾個優點。一種是模式識別受體，當它受到激動時，可以弱極化一些腫瘤支持的巨噬細胞，並將它們轉化為腫瘤破壞性巨噬細胞。

From an expression standpoint, Dectin-2 is actually quite interesting because it is elevated in tumor-associated myeloid cells, which include macrophages and other cell types and its expression is relatively modest in the rest of the body such that you can get some nice tumor targeting with the BDC-3042. And that's why we're excited about this program.

從表達的角度來看，Dectin-2 實際上非常有趣，因為它在腫瘤相關骨髓細胞（包括巨噬細胞和其他細胞類型）中表達升高，而它在身體其他部位的表達相對溫和，因此您可以獲得一些好的腫瘤使用 BDC-3042 進行定位。這就是我們對這個計劃感到興奮的原因。

Certainly, from other TAM-targeting agents that are out there, we are certainly aware of the previous strategies geared mostly towards depleting some of these tumor-associated macrophages and we believe very much in redeeming these cells and reprogramming and such that they can really fight for us rather than against us in the tumor.

當然，從現有的其他 TAM 標靶藥物中，我們當然知道以前的策略主要是為了耗盡一些與腫瘤相關的巨噬細胞，我們非常相信可以挽救這些細胞並重新編程，這樣它們就可以真正對抗腫瘤對我們有利而不是對我們不利。

And I would say some of the interesting ones are certainly CD40 agonist that have had some early compelling clinical activity that were really hampered or hindered rather by some of the potential toxicity of targeting CD40 such that it has pretty broad expression in the periphery and across the body. So that's why we think the targeting of Dectin-2, which is more specific to the tumor, is compelling.

And I would say some of the interesting ones are certainly CD40 agonist that have had some early compelling clinical activity that were really hampered or hindered rather by some of the potential toxicity of targeting CD40 such that it has pretty broad expression in the periphery and across the身體.這就是為什麼我們認為 Dectin-2 的標靶作用非常引人注目，因為它對腫瘤更具特異性。

Thank you. There are no further questions. I could turn the call back over to Willie Quinn for any further remarks.

謝謝。沒有其他問題了。我可以將電話轉回給威利·奎因以徵求進一步意見。

Thank you. So this has been an emotional day for us, as you can imagine. And we thank you all for joining us today, and we look forward to keeping you updated on our programs and hope to talk to you again soon. Thank you.

謝謝。因此，正如你可以想像的那樣，這對我們來說是激動人心的一天。我們感謝大家今天加入我們，我們期待向您通報我們計劃的最新情況，並希望很快能再次與您交談。謝謝。

Thank you for your participation. This does conclude the program. You may now disconnect. Everyone, good day.

感謝您的參與。這確實結束了該程式。您現在可以斷開連線。大家，美好的一天。