Ispinesib

4月20日，Vincerx Pharma在2023年美国癌症研究协会（AACR）年会上展示了其自研药物VIP924的临床前数据。据Vincerx Pharma宣称，CXCR5是一个非常有潜力的药物靶点，用于开发治疗淋巴瘤患者的抗体-药物偶联物（antibody-drug conjugates，ADC）。 淋巴瘤是起源于淋巴造血系统的恶性肿瘤，主要表现为无痛性淋巴结肿大，肝脾肿大，全身各组织器官均可受累。根据瘤细胞分为非霍奇金淋巴瘤（NHL）和霍奇金淋巴瘤（HL）两类。病理学特征在霍奇金淋巴瘤为瘤组织内含有淋巴细胞、嗜酸性粒细胞、浆细胞和特异性的里-斯（Reed-Steinberg）细胞，HL按照病理类型分为结节性富含淋巴细胞型和经典型，后者包括淋巴细胞为主型、结节硬化型、混合细胞型和淋巴细胞消减型。 NHL发病率远高于HL，是具有很强异质性的一组独立疾病的总和，病理上主要是分化程度不同的淋巴细胞、组织细胞或网状细胞，根据NHL的自然病程，可以归为三大临床类型，即高度侵袭性、侵袭性和惰性淋巴瘤。根据不同的淋巴细胞起源，可以分为B细胞、T细胞和NK细胞淋巴瘤。 VIP924由抗CXCR5的人源化单克隆抗体组成，该药物含有一个独特的肽序列，能被肿瘤相关的溶酶体蛋白酶legumain特异性裂解。在肿瘤细胞内，当legumain裂解时，活性载荷成分VIP716被释放。VIP716是一种新型的，高效且特异的纺锤体驱动蛋白（KSPi）抑制剂，通过被修饰为亲水的CellTrapper™分子，以减少药物膜渗透性，而降低药物的负面效应。这种修饰使VIP716在CXCR5+肿瘤细胞中的细胞质内积聚，以提供更大的疗效，并防止药物渗透到健康组织中，减少毒性。 Vincerx Pharma的数据显示：通过免疫组化法观察到CXCR5在新发和再发弥漫性大B细胞淋巴瘤（DLBCL）、滤泡性淋巴瘤（FL）、套细胞淋巴瘤（MCL）和慢性淋巴细胞白血病（CLL）样本中的高表达；而在健康组织中表达有限。 VIP924在不同的非霍奇金淋巴瘤细胞系中显示出卓越的体外细胞毒性，与其他偶联相同化学效应物的B细胞淋巴瘤靶向抗体，包括CD19-KSPi、CD22-KSPi和CD70-KSPi相比， VIP924（10mg/kg）在两种DLBCL衍生的动物肿瘤模型中产生了明显的肿瘤生长抑制作用：在一个低CXCR5表达的模型中为68%，在一个高CXCR5表达的模型中为87%。在两个VIP924治疗的动物模型中，动物存活时间均延长。在VIP924治疗的小鼠中没有观察到对药物体重的影响或任何不良反应。 为了确定VIP924对较大规模肿瘤的疗效，在移植了HBL-1淋巴瘤细胞系的小鼠中，给予单次10mg/kg的VIP924剂量。3只小鼠中的2只观察到完全反应，在治疗第26天没有观察到可测量的肿瘤。24和48小时后，在肿瘤中检测到VIP924代谢物VIP716的积累，而在血浆中没有检测到。 KSP抑制导致有丝分裂停止，并形成特征性的单极纺锤体（monoasters）。与可渗透的小分子KSPi Ispinesib相比，VIP924治疗淋巴瘤细胞系中产生了更高的水平和更长的单体形成时间。 Vincerx公司首席执行官Ahmed Hamdy医学博士评论："我们很高兴能用我们最新的我们的生物标记平台继续推进ADC药物VIP924的研究。VIP924在一组淋巴瘤细胞系以及细胞系衍生和患者衍生的淋巴瘤小鼠模型中显示了有意义的临床前活性。最值得注意的是，植入淋巴瘤患者肿瘤细胞的小鼠模型在VIP924治疗后显示出明显的肿瘤生长抑制和生存期延长。在植入患者肿瘤细胞的小鼠模型（也称为PDX模型）中显示出药物活性有特别意义，因为PDX模型比细胞系的试验结果更能代表人类癌症的复杂性。" 参考资料：https://investors.vincerx.com/news-releases/news-release-details/vincerx-pharma-presents-preclinical-data-vip924-first-class

PALO ALTO, Calif., April 19, 2023 (GLOBE NEWSWIRE) -- Vincerx Pharma Inc. (Nasdaq: VINC), a biopharmaceutical company aspiring to address the unmet medical needs of patients with cancer through paradigm-shifting therapeutics, today presented a poster of VIP924 preclinical data at the 2023 American Association for Cancer Research (AACR) Annual Meeting. VIP924 consists of an anti-CXCR5 humanized monoclonal antibody with a novel linker containing a unique peptide sequence specifically cleaved by legumain—a tumor-associated lysosomal protease. Inside the tumor cell, upon legumain cleavage, the active payload, VIP716, is released. VIP716 is a novel highly potent and selective kinesin spindle protein inhibitor (KSPi), which has been modified with a hydrophilic CellTrapper™ moiety to reduce membrane permeability without having a negative impact on efficient target binding. This modification allows for intracellular accumulation of VIP716 in CXCR5+ tumor cells, providing greater efficacy, and prevents cellular penetration into healthy tissues, reducing toxicity. “We are thrilled to continue advancing our bioconjugation platform with our newest ADC, VIP924,” said Ahmed Hamdy M.D., Chief Executive Officer of Vincerx. “At AACR, VIP924 showed meaningful preclinical activity in a panel of lymphoma cell lines and in cell line-derived and patient-derived lymphoma mouse models. Most notably, mouse models implanted with tumor cells from lymphoma patients demonstrated significant tumor growth inhibition and prolonged survival after VIP924 treatment. Showing activity in mouse models implanted with tumor cells from patients, also known as PDX models, is particularly meaningful because PDX models are more representative of the complexity of human cancer than results seen with cell lines.” Dr. Hamdy continued, “Despite progress in the treatment of B-cell malignancies, there is still an unmet medical need, especially for patients with relapsed or refractory disease. The results presented at AACR, together with our previous efficacy findings of durable complete tumor regression in CXCR5-positive, ibrutinib-refractory lymphoma models, suggest that VIP924 has the potential to be a treatment option for relapsed and refractory patients. Looking at the totality of preclinical data we’ve generated, including the data we presented at ASH that showed how our next generation linker, payload, and CellTrapper™ technology significantly improved the safety and efficacy of the approved ADC, Mylotarg™, we can’t help but be excited about the future of our ADC programs. We look forward to filing the IND for VIP924 in mid-2024.” Key Presentation Highlights: Poster presentation, titled, CXCR5 is a very promising drug target for the development of antibody-drug conjugates to treat patients with lymphoma, presented by Tibor Schomber, Ph.D., Vincerx Pharma GmbH, Monheim, Germany, include: High expression of CXCR5 was observed by immunohistochemistry on naive and previously treated diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and chronic lymphocytic leukemia (CLL) samples; with limited expression in healthy tissues. VIP924 showed superior in vitro cytotoxicity across different non-Hodgkin lymphoma cell lines compared with other B-cell lymphoma targeting antibodies conjugated to the same effector chemistry including, CD19-KSPi, CD22-KSPi, and CD70-KSPi. VIP924 (10mg/kg) resulted in significant tumor growth inhibition in two DLBCL patient-derived tumor models: 68% in a low CXCR5-expressing model and 87% in a high CXCR5-expressing model. Prolonged survival of VIP924-treated animals was observed in both models. No effect on body weight or any adverse effects in the VIP924-treated mice were observed. To determine the efficacy of VIP924 in large, established tumors, a single VIP924 dose of 10mg/kg was administered in mice transplanted with the HBL-1 lymphoma cell line. Complete responses were observed in 2 out of 3 mice with no measurable tumors on treatment day 26. After 24 and 48 hours, accumulation of VIP716 (ie, payload; “metabolite”) was observed in the tumors but not in plasma. KSP inhibition resulted in mitotic arrest and the formation of characteristic monopolar spindles (monoasters). VIP924 treatment produced higher levels and longer duration of monoaster formation in a lymphoma cell line compared to the permeable, small molecule KSPi, ispinesib. The poster can be accessed on the presentations section of the Vincerx website. About Vincerx Pharma, Inc. Vincerx Pharma, Inc. (Vincerx) is a clinical-stage biopharmaceutical company committed to developing differentiated and novel therapies to address the unmet medical needs of patients with cancer. Vincerx has assembled a seasoned management team with a proven track record of successful oncology drug development, approvals, and value creation. The company’s diverse pipeline consists of enitociclib, currently in Phase 1, and a proprietary modular bioconjugation platform, which includes a small molecule drug-conjugate, VIP236, in Phase 1, and preclinical next-generation antibody drug conjugates, VIP943 and VIP924. Vincerx is based in Palo Alto, Calif., and has a research facility in Monheim, Germany. For more information, please visit . Cautionary Statement This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended (the “Securities Act”), and Section 21E of the Securities Exchange Act of 1934, as amended, that are intended to be covered by the “safe harbor” created by those sections. Forward-looking statements, which are based on certain assumptions and describe future plans, strategies, expectations and events, can generally be identified by the use of forward-looking terms such as “believe,” “expect,” “may,” “will,” “should,” “would,” “could,” “suggest,” “seek,” “intend,” “plan,” “goal,” “potential,” “on-target,” “on track,” “project,” “estimate,” “anticipate,” or other comparable terms. All statements other than statements of historical facts included in this press release are forward-looking statements. Forward-looking statements include, but are not limited to: Vincerx’s business model, pipeline, strategy, timeline, product candidates and attributes, and preclinical and clinical development, timing, and results. Forward-looking statements are neither historical facts nor assurances of future performance or events. Instead, they are based only on current beliefs, expectations and assumptions regarding future business developments, future plans and strategies, projections, anticipated events and trends, the economy and other future conditions. Forward-looking statements are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict and many of which are outside of our control. Actual results, conditions and events may differ materially from those indicated in the forward-looking statements. Therefore, you should not rely on any of these forward-looking statements. Important factors that could cause actual results, conditions, and events to differ materially from those indicated in the forward-looking statements include, but are not limited to: general economic, financial, legal, political, and business conditions; the potential effects of health epidemics and pandemics, including COVID-19; risks associated with preclinical or clinical development and trials, including those conducted prior to Vincerx’s in-licensing; failure to realize the benefits of Vincerx’s license agreement with Bayer; risks related to the rollout of Vincerx’s business and the timing of expected business milestones; changes in the assumptions underlying Vincerx’s expectations regarding its future business or business model; Vincerx’s ability to develop and commercialize product candidates; Vincerx’s capital requirements and availability and uses of capital; and the risks and uncertainties set forth in Forms 10-K, 10-Q, and 8-K most recently filed with or furnished to the SEC by Vincerx. Forward-looking statements speak only as of the date hereof, and Vincerx disclaims any obligation to update any forward-looking statements. Vincerx and the Vincerx logo are our trademarks. This press release also contains trademarks and trade names that are the property of their respective owners. Contacts Gabriela Jairala Vincerx Pharma, Inc. gabriela.jairala@vincerx.com Bruce Mackle LifeSci Advisors, LLC 646-889-1200 bmackle@lifesciadvisors.com