Crenigacestat

针对这一问题，研究人员系统性阐明了CD51作为肿瘤转移关键分子，存在一种潜在的作用机制“逃逸”了西仑吉肽的抑制作用。具体而言，CD51可接受γ-分泌酶(γ-secretase)介导的跨膜切割并产生游离 近日，中山大学附属第三医院杨扬教授肝脏外科团队与中山大学中山医学院项鹏教授团队合作在肝脏病学顶级期刊Journal of Hepatology在线发表题为“Combined inhibition of surface CD51 and γ-secretase-mediated CD51 cleavage improves therapeutic efficacy in experimental metastatic hepatocellular carcinoma”的研究论文。 该研究发现整合素家族蛋白CD51促进肝细胞癌远处转移的全新机制，为以整合素为靶点的综合肿瘤治疗提供了重要理论支撑，开拓了未来发展思路，具有很强的临床转化价值。中山大学附属第三医院肝脏外科学科带头人杨扬教授，中山大学中山医学院项鹏教授作为共同通讯作者。 肝细胞癌（hepatocellular carcinoma, HCC）作为全球第二大致死恶性肿瘤，在确诊时往往已伴发远处转移，严重限制了肝癌患者预后。然而针对其远处转移，目前可用的治疗手段十分有限。进一步明确肝癌在远处转移中的关键环节，进而开发相应的靶向治疗策略，对改善晚期肝癌患者预后至关重要。 由于HCC患者通常有明确的前驱病理学改变，即“肝炎-肝硬化-肝癌”三部曲，超过80%的HCC患者具有纤维化或肝硬化背景。针对这一特征，大量研究证实了纤维化肿瘤微环境与肝癌恶性进展及患者预后的高度相关性。作为主要胞膜蛋白家族之一，整合素家族是肿瘤细胞与微环境密切通讯的关键媒介，对于多种实体肿瘤侵袭、转移均具有促进作用。也因此，整合素家族被认为是极具前景的晚期肿瘤治疗靶点。其中，针对整合素αv（CD51）的药物开发与临床试验最为火热。以西仑吉肽（cilengitide）作为代表的小分子CD51抑制剂在临床前及早期临床研究中均表现出良好的安全性及抗肿瘤效果。然而，在大规模III期临床研究中，cilengitide却并未展现出有效的抗肿瘤效应，研究最终以失败告终，失败的原因也尚未阐明。 针对这一问题，研究人员系统性阐明了CD51作为肿瘤转移关键分子，存在一种潜在的作用机制“逃逸”了西仑吉肽的抑制作用。具体而言，CD51可接受γ-分泌酶(γ-secretase)介导的跨膜切割并产生游离的CD51胞内结构域（CD51-ICD）。而CD51-ICD能够“忽视”西仑吉肽的抑制作用而独立发挥促肿瘤效应。进一步，研究人员通过多种临床相关动物模型发现当联合γ-分泌酶抑制剂LY3039478时，以西仑吉肽为基础的治疗显示出显著改善的抗肿瘤效应。这一发现提示西仑吉肽及LY3039478联合疗法是一种具有前景的肝癌治疗策略，为在临床环境中重新评估西仑吉肽提供了理论基础，并强调了在未来针对CD51的临床试验中确定更精确的患者亚群的重要性。 机制模式图

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