HPN-536

点击上方的 行舟Drug ▲ 添加关注前言迄今为止，与传统的抗癌治疗策略相比，免疫治疗被认为是最有前景的全身性肿瘤治疗方法，在提高治疗效果方面发挥着不可或缺的作用，尤其是对难治性癌症的治疗。新兴的癌症免疫疗法包括癌症疫苗、嵌合抗原受体的T细胞（CAR-T）治疗、细胞因子治疗、免疫检查点抑制剂和双特异性抗体（BsAbs）。其中，双特异性抗体因其针对多个靶点的能力，已成为癌症治疗中一种关键和有效的治疗方式。然而，尽管FDA批准的第一种针对B细胞恶性肿瘤的双特异性抗体（blinatumomab）在临床上取得了成功，但仍存在许多障碍，如治疗耐药性和对实体瘤差强人意的效果。为了克服这些局限性，人们致力于开发多特异性抗体。截至2022年11月，约有20个具有三种（甚至四种）特异性的分子实体处于治疗血液系统恶性肿瘤或实体瘤的早期临床试验中。这些多特异性抗体的开发和应用，为解决癌症的复杂生物学和抗肿瘤免疫反应的发生开辟了新的途径。多特异性抗体的设计多特异性抗体通过同时结合不同的抗原或表位而表现出多重特异性，其大致分为两类：（a）IgG样（有Fc区）和（b）非IgG样（无Fc区）。具有Fc区的IgG样多特异性抗体由于其较大的尺寸和FcRn介导的再循环过程，比没有Fc区域的多特异性抗体具有更长的循环半衰期。纯化更方便，溶解度和稳定性提高。更重要的是，它可能具有更大的临床治疗潜力，以保留多种Fc介导的效应器功能，包括抗体依赖性细胞毒性（ADCC)、补体依赖性细胞毒性(CDC)和Ab依赖性细胞吞噬作用。非IgG样多特异性抗体相比之下，显示出相对较低的循环动力学，但具有更好的组织穿透能力，较低的免疫原性，以及较低的固有免疫系统的非特异性激活。这种形式的多特异性抗体主要依赖于其抗原结合能力发挥多种功能。T细胞接合器（TCE）的多特异性抗体免疫细胞接合器是能够重定向免疫效应细胞对抗癌症细胞的分子，其目的是触发有效的肿瘤细胞杀伤，充当免疫细胞和靶细胞之间的桥梁。Catumaxomab和blinatumomab是首个获批临床使用的T细胞接合器，均具有双特异性格式，并包括用于T细胞重定向的抗CD3部分。添加第三个结合域使T细胞结合器具有了新的功能，包括增强肿瘤特异性或增强免疫细胞激活。增加第二个抗体结合部分以靶向相同肿瘤细胞上表达的不同TAA提供了额外的优势。与传统的单TAA靶向TCE相比，双TAA靶向可有助于防止由选择性压力引起的肿瘤逃逸，并可帮助克服抗原异质性。双TAA靶向TCE已被设计用于白血病细胞杀伤，这是CD19/CD3 BiTE的进化形式。这种多特异性抗体在B-ALL患者中显示出显著的疗效。此外，为了克服潜在地CD19抗原逃逸，研究人员将第二种抗CD20 scFv添加到CD19/CD3 TCE中。在另一项工作中，通过将抗CD19 scFv和抗CD22 sdAb融合设计了CD19/CD22/CD3 TsAb。与单独或组合的相应BsAb相比，在B-ALL的患者来源的PDX模型中显示出显著增强的抗肿瘤功效。NK细胞接合器（TCE）的多特异性抗体靶向一个（或两个）激活NK细胞受体和TAA的多特异性分子构成了另一种免疫细胞接合器，其被开发用于增强NK细胞对肿瘤细胞的识别和杀伤。在激活的NK细胞受体中，触发静止NK细胞激活的能力上，CD16>NKp46>NKG2D。与TCE一样，NKCE抗体中也实现了与两种不同TAA的同时结合，以增加其治疗窗口。例如，将额外的抗CD19 scFv添加到CD19/CD16的BsAb中。第二种肿瘤结合scFv的加入提高了对CD19+白血病细胞的亲和力，促进了NK介导的抗体依赖性细胞毒性，并改善了血清半衰期。另外，用TsAb CD33/CD16/CD123进行AML细胞的双重靶向，其诱导NK细胞对原发性白血病细胞的裂解能力明显强于三价BsAb CD123/CD16/CD123。靶向两种共刺激或检查点受体的接合器用抗CD3对T细胞的抗原非依赖性刺激已经被证实。然而另一方面，单价CD3诱导T细胞活化必须伴随着协同刺激信号，以实现最佳激活和T细胞增殖。此外，活化的T细胞反过来表达抑制性检查点受体以控制免疫反应。因此，三特异性TCE的设计，包括共刺激分子的激动剂或检查点受体的拮抗剂，以及抗CD3和抗TAA部分，构成了另一种策略。这些分子包括共刺激受体CD28（TAA/CD3/CD28）的激动剂。研究发现，TsAb上抗CD28结构域的存在增强了体外不同多发性骨髓瘤（MM）细胞系的T细胞活化和杀伤，远高于daratumumab的效力。同样，TsAb在人源化的MM小鼠模型中表现得更好，即使在最低剂量下也是如此。基于同一平台的第二个TsAb HER2/CD3/CD28最近进入了临床试验。在人源化乳腺癌模型中，这种TsAb介导有效的肿瘤消退，即使在HER2表达较低的肿瘤中，也表明对目前不适合抗HER2治疗的乳腺癌症患者有潜在益处。NK细胞的充分激活以诱导抗肿瘤免疫已被证明需要不同细胞表面受体的共同参与。基于这一考虑，已经设计了一系列结合TAA并触发两个NK细胞活化受体的分子。例如，TriNKET（三特异性NKCE疗法），DF1001是属于该平台的几种药物之一，其靶向HER2/CD16/NKG2D。这种HER2靶向TriNKET的安全性和有效性正在一项1/2期试验中研究，该试验针对各种晚期HER2+实体瘤患者，单独或与免疫检查点抑制剂联合使用。另一种是多特异性抗体是基于IL-15的三功能NK细胞接合器，它用一个臂结合TAA，用另一个臂连接CD16，而它们的第三部分是IL-15，它通过与相应受体的相互作用激活招募的NK细胞。文献报道的第一个基于IL-15的TriKE是CD33/IL-15/CD16，它诱导了针对CD33+AML细胞系优异的NK细胞毒性、脱颗粒和细胞因子产生，并增加了NK细胞的体外存活和增殖。在小鼠肿瘤模型中，也显示出相对于BiKE增强的抗肿瘤活性。其他的TriKE还包括针对EpCAM、CD133以及CD19等。靶向多种受体的多特异性抗体除了免疫细胞接合器，另一种多特异性抗体识别在同一细胞表面表达的不同抗原，不会桥接肿瘤和效应细胞。Amivantamab可识别EGFR和cMet并阻断其各自的信号通路，于2021被批准用于EGFR外显子20插入突变的非小细胞肺癌的治疗。在TsAb中掺入第三个结合结构域可能会提高其效力。例如，研究人员已经设计获得了HER2/EGFR/cMet的TsAb，TsAb被设计为具有不同的几何形状，每个构建体都表现出强烈的三特异性结合，它们的治疗潜力仍有待检测。多重肿瘤靶向的另一个例子是针对EGFR、IGF1R和cMet或HER3的IgG样TriMAb。在将TriMAb活性与单个抗体或组合进行比较的增殖测定中，观察到EGFR/IGF1R/HER3 TriMAb更优异的生长抑制作用。另一种多特异性抗体GB263T，一种识别EGFR的IgG样TsAb和两种不同的cMET表位，具有增强的ADCC功能。在几种EGFR外显子20插入、EGFR C797S突变、cMET扩增和cMET外显子14跳跃突变的肿瘤模型中，GB263T的体内抗肿瘤效果显著。目前，GB263T正在1期临床研究（NCT05332574）中进行测试。最后，人们也开始尝试基于TsAb的免疫偶联物进行药物、毒素或放射性同位素的肿瘤递送，从而潜在地增加选择性，从而增加其治疗窗口。为延迟半衰期而设计的多特异性抗体多特异性抗体的另一种形式包括增加血清半衰期的部分。包含白蛋白结合sdAb是小分子量治疗药物广泛使用的半衰期延长策略。由于白蛋白的大小和FcRn介导的再循环，其血清半衰期为3周，与标准IgG抗体相同。在临床前研究中，已经在不同物种中证明了通过与白蛋白结合的sdAb融合而延长抗体片段的半衰期。目前在临床试验中有相当比例的TsAb已经使用该策略延长了半衰期。例如，分子量约为53kDa的单链TriTAC形式包含N端人源化抗TAA sdAb和C端人源性抗CD3 scFv，由抗白蛋白sdAb连接，这为TriTAC提供了延长的血清半衰期。截至2022年11月，四种TriTAC正在进行早期临床试验：抗BCMA的HPN217用于MM，抗DLL3 的HPN328用于小细胞肺癌（SCLC），HPN424用于前列腺癌症，HPN536用于间皮素阳性实体瘤。Humabody CB307也采用了类似的策略，使用三种全人源sdAb靶向PSMA、CD137和HSA，目前正处于治疗晚期PSMA+肿瘤的I期试验。基于相同的技术，CB213是一种四价三特异性Humabody，同时在T细胞和HSA上接合PD1和LAG-3。与抗PD1单抗相比，CB213显示出优越的活性，以诱导来自NSCLC患者的T细胞体外增殖并抑制体内肿瘤生长。此外，NHP药代动力学表明可能每周进行一次临床给药，考虑到这些分子的小尺寸，这是一个有利的方案。开发中的多特异性抗体在过去的30年里，人们目睹了一个巨大的转变，从仅仅开发和改造基本的Abs，发展到更复杂的Ab衍生物、双抗以及最近快速发展中的多特异性抗体。目前，已有多项多特异性抗体处于临床前和临床开发阶段，下面的两个表格罗列了部分临床前和临床开发中的多特异性抗体。小结目前的临床前和早期临床数据表明，多特异性抗体相比双抗在增加免疫细胞的效力，针对肿瘤内异质性和不利的肿瘤微环境方面，具有更强的优势。同时，多特异性抗体在可制造性方面也提出了重要挑战，某些结构可能会受到稳定性的影响，导致断裂和聚集。此外，多链多特异性抗体的生产可能会受到由于错误组装而产生的非预期副产物的阻碍。这些问题都需要优化符合良好制造规范的工艺以解决。参考文献：1.When three is not a crowd: trispecific antibodies for enhanced cancer immunotherapy. Theranostics. 2023; 13(3): 1028–1041.文章信息源于公众号小药说药，登载该文章目的为更广泛的传递行业信息，不代表赞同其观点或对其真实性负责。文章版权归原作者及原出处所有，文章内容仅供参考。本网拥有对此声明的最终解释权，若无意侵犯版权，请联系小编删除。学如逆水行舟，不进则退；心似平原走马，易放难收。行舟Drug每日更新 欢迎订阅+医药大数据|行业动态|政策解读

Enrollment for HPN217 (BCMA) and HPN328 (DLL3) remain on track, with data updates and selection of recommended Phase 2 doses for both ongoing clinical programs planned in 2023 Five preclinical posters presented at AACR 2023 in April on HPN217, HPN328 and ProTriTAC™ development candidates Following $25 million financing in March, cash and equivalents of $61.4 million expected to fund current operations into second half of 2024 SOUTH SAN FRANCISCO, Calif., May 11, 2023 (GLOBE NEWSWIRE) -- Harpoon Therapeutics, Inc. (Nasdaq: HARP), a clinical-stage immuno-oncology company developing novel T cell engagers, today reported financial results for the first quarter ended March 31, 2023 and provided a corporate update. “Harpoon is executing its business plan in 2023 with a strengthened balance sheet, advancing multiple programs based on the TriTAC® platform, and ProTriTAC™ IND candidates ready for further development,” said Julie Eastland, President and Chief Executive Officer of Harpoon Therapeutics. “Following the $25 million preferred equity financing in March 2023, we have the financial strength to fund current operations into the second half of 2024. Additionally, we expect to see a positive impact on our cash burn over the course of the year from the restructuring implemented in the fourth quarter of last year. We also anticipate completion of enrollment for two of our Phase 1 clinical programs, HPN217 and HPN328, and achievement of key data milestones this year. Our clinical and leadership teams remain focused on advancing a rich pipeline of next-generation T cell engagers to address a broad patient population with unmet needs in both solid tumor and blood cancer indications.” Corporate Update / Recent and Upcoming Highlights Tri-specific T cell Activating Construct (TriTAC®) PlatformHPN217 (BCMA) Phase 1 trial for relapsed, refractory multiple myeloma Interim results reported at the 64th American Society of Hematology (ASH) Annual Meeting (cut-off of October 17, 2022) demonstrated continued evidence of clinical activity with 77% (10/13) ORR observed in the two highest target dose levels (12 and 24 mg).Overall low incidence of cytokine release syndrome (CRS) across the patient population studied to date.Completion of Phase 1 dose exploration is expected in the first half of 2023, with identification of a recommended Phase 2 dose(s) expected by the end of 2023.Data presentation anticipated in the second half of 2023. HPN328 (DLL3) Phase 1/2 trial in small cell lung cancer (SCLC) and neuroendocrine cancers Observations in the monotherapy cohorts, as of February 2023, included early signs of anti-tumor activity, with two confirmed partial responses per RECIST in patients with SCLC.Phase 1/2 dose and schedule optimization trial ongoing with monotherapy cohorts enrolling at the 24 mg target dose.Enrollment in combination therapy of HPN328 with atezolizumab (Tecentriq®) in patients with SCLC, as part of the Phase 1/2 dose escalation trial, is anticipated to begin in the second half of 2023.Phase 1 dose exploration is expected to complete in the second half of 2023, including the identification of a recommended Phase 2 dose(s) in the monotherapy setting by the end of 2023.Data presentation anticipated in the second half of 2023. ProTriTAC™ HPN601 (EpCAM) HPN601 is Harpoon’s first conditionally active T cell engager based on the ProTriTAC™ platform. EpCAM is expressed in a broad range of solid tumors, potentially enabling HPN601 to address multiple indications with high unmet medical need.IND filing timeline to enable a Phase 1 dose exploration study dependent on resource allocation. Two additional candidates Two new candidates for potential IND-enabling studies from the ProTriTAC platform have been identified against the targets trophoblast cell surface antigen 2 (TROP2) and Integrin-β6 (ITGB6). TriTAC-XR® The proprietary TriTAC-XR extended-release T cell engager platform is designed to minimize on-target CRS, a characteristic of many T cell engagers that can lead to dose limiting toxicities and can reduce the efficacy of these potent anti-tumor drugs. AACR 2023 – Five Preclinical Posters Presented HPN217: Poster presented on April 18, 2023: “Anti-tumor activity of HPN217, a BCMA-targeting tri-specific T cell engager, is enhanced by γ-secretase inhibitors in preclinical models” In preclinical mouse models, γ-secretase inhibitors increased the potency of HPN217 in vitro in multiple cell lines.Combination therapy with 1mg/kg LY-3039478 and a subtherapeutic dose of 4ug/kg HPN217 led to decreased tumor burden and increased survival in a disseminated MOLP8 xenograft compared to either monotherapy alone. HPN328: Two posters presented on April 18, 2023: “Long-term anti-tumor immunity induced by HPN328, a DLL3-targeting tri-specific, half-life extended T cell engager, in a preclinical immunocompetent mouse model” These results suggest that HPN328 can induce epitope spreading and prolonged anti-tumor immunity, with an increase in memory T cells, suggesting a novel mechanism for its activity and efficacy in vivo. These findings suggest that long-term anti-tumor immunity induced by HPN328 can potentially lead to more durable anti-tumor responses in cancer patients “Anti-tumor activity of HPN328, a DLL3-targeting tri-specific, half-life extended T cell engager, is enhanced by combining with an anti-PD-L1 antibody in an immunocompetent mouse model” These results demonstrate the utility of combining anti-PD-L1 antibodies to enhance the anti-tumor activity of HPN328 and further supports investigation of this combination approach in patients.Clinical studies of HPN328 in combination with atezolizumab are planned. ProTriTAC™: Two posters presented on April 17, 2023 introducing new candidates for IND-enabling studies: “TROP2 ProTriTAC™, a protease-activated T cell engager prodrug targeting TROP2 for the treatment of solid tumors”“ITGB6 ProTriTAC™, a protease-activated T cell engager prodrug targeting Integrin-β6 for the treatment of solid tumors”Both data sets support further investigation of Harpoon’s conditionally active next-generation T cell engager platform, ProTriTAC™, with demonstrated therapeutic potential in a broad range of TROP2- and ITGB6-expressing solid tumors. Corporate Update $25 million preferred equity financing closed in March 2023, extending cash runway into the second half of 2024. First Quarter 2023 Financial Results Harpoon ended the first quarter of 2023 with $61.4 million in cash and cash equivalents compared to $53.1 million as of December 31, 2022. Following the $25.0 million preferred equity financing and year to date ATM sales, cash and cash equivalents are expected to fund current operations into the second half of 2024. Revenue for the quarter ended March 31, 2023 was $8.6 million, compared to $5.9 million for the first quarter ended March 31, 2022. The increase in revenue was primarily due to revenue recognized in first quarter 2023 for research and development services performed on the fourth target under Harpoon’s Restated Collaboration Agreement with AbbVie, and an increase in revenue recognized related to Harpoon’s Development and Option Agreement with AbbVie for research and development services performed.Research and development (R&D) expense for the quarter ended March 31, 2023 was $15.2 million, reduced from $20.8 million during the first quarter ended March 31, 2022. The decrease primarily arose from lower personnel-related costs due to corporate restructuring implemented in November 2022 and lower clinical and development costs due to the wind down of the HPN424 and HPN536 programs.General and administrative (G&A) expense for the quarter ended March 31, 2023 decreased to $4.2 million, compared to $5.4 million for the first quarter ended March 31, 2022. The decrease was primarily attributable to lower personnel-related expenses, lower legal costs, and lower professional service fees to support Harpoon’s operations. Net loss for the first quarter ended March 31, 2023 was $11.3 million, improved from $20.3 million for the first quarter ended March 31, 2022. About Harpoon Therapeutics Harpoon Therapeutics is a clinical-stage immuno-oncology company developing a novel class of T cell engagers that harness the power of the body’s immune system to treat patients suffering from cancer and other diseases. T cell engagers are engineered proteins that direct a patient’s own T cells to kill target cells that express specific proteins, or antigens, carried by the target cells. Using its proprietary Tri-specific T cell Activating Construct (TriTAC®) platform, Harpoon is developing a pipeline of novel TriTACs initially focused on the treatment of solid tumors and hematologic malignancies. Harpoon has also developed a proprietary ProTriTAC™ platform, which applies a prodrug concept to its TriTAC platform to create a therapeutic T cell engager that remains inactive until it reaches the tumor. Harpoon’s third proprietary technology platform, extended release TriTAC-XR, is designed to mitigate cytokine release syndrome. For additional information about Harpoon Therapeutics, please visit www.harpoontx.com. Cautionary Note on Forward-looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as “anticipate,” “may,” “expect,” “plan,” “potential,” “further,” “will,” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. These forward-looking statements are based on Harpoon Therapeutics’ expectations and assumptions as of the date of this press release. Each of these forward-looking statements involves risks and uncertainties that could cause Harpoon Therapeutics’ clinical development programs, future results or performance to differ significantly from those expressed or implied by the forward-looking statements. Forward-looking statements contained in this press release include, but are not limited to, statements about the expected progress, results, and plans pertaining to Harpoon Therapeutics’ clinical trials, including timing, scope, design and interim results of clinical trials and the safety and tolerability profile of product candidates, the association of interim clinical data and preclinical results with potential treatment outcomes, achievement of future milestones, cash sufficiency forecasts, including ability to extend cash runway as a result of the restructuring and financing activities, and other statements that are not historical fact. Many factors may cause differences between current expectations and actual results, including unexpected safety or efficacy data observed during clinical studies, preliminary data and trends may not be predictive of future data or results, may not demonstrate safety or efficacy or lead to regulatory approval by the FDA or other regulatory agencies, clinical trial site activation or enrollment rates that are lower than expected, changes in expected or existing competition, changes in the regulatory environment, the uncertainties and timing of the regulatory approval process, the timing and results of unexpected litigation or other disputes, and the sufficiency of Harpoon Therapeutics’ cash resources, including that Harpoon Therapeutics may not achieve the expected benefits of its restructuring or may incur unexpected additional expenses in connection with such restructuring. These and other factors that may cause Harpoon Therapeutics’ actual results to differ from those expressed or implied in the forward-looking statements in this press release are discussed in Harpoon Therapeutics’ filings with the U.S. Securities and Exchange Commission, including under “Risk Factors” in Harpoon Therapeutics’ quarterly report on Form 10-Q for the quarter ended March 31, 2023, and future filings by Harpoon Therapeutics. Except as required by law, Harpoon Therapeutics assumes no obligation to update any forward-looking statements contained herein to reflect any change in expectations, even as new information becomes available. Contacts: Investors:ICR WestwickeRobert H. Uhl619-228-5886 robert.uhl@westwicke.com Media:uncapped Communications303-588-0599kerry.walton@uncappedcommunications.com Harpoon Therapeutics, Inc.Statement of Operations and Comprehensive Loss(Unaudited) (in thousands, except share and per share amounts) For the Three Months Ended March 31, 2023 2022 Revenue Collaboration and license revenue $8,583 $5,906 Total revenue 8,583 5,906 Operating expenses Research and development 15,163 20,818 General and administrative 4,185 5,401 Total operating expenses 19,348 26,219 Loss from operations (10,765) (20,313)Interest income, net 425 40 Interest expense (138) — Other expense, net (860) (48)Net loss attributable to common stockholders (11,338) (20,321)Other comprehensive loss: Net unrealized loss on marketable securities 3 (41)Comprehensive loss $(11,335) $(20,362)Net loss attributable to common stockholders per share, basic and diluted (0.31) (0.62)Weighted-average shares used in computing net loss per share, basic and diluted 36,968,214 32,879,188 Harpoon Therapeutics, Inc.Selected Balance Sheet Data(Unaudited) March 31,2023 December 31,2022 (in thousands) Cash and cash equivalents $61,385 $53,112 Total assets $80,809 $73,729 Total liabilities $80,094 $68,330 Total stockholders' equity $715 $5,399