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PALO ALTO, Calif., Sept. 14, 2023 (GLOBE NEWSWIRE) -- Vincerx Pharma Inc. (Nasdaq: VINC)(“Vincerx”), a biopharmaceutical company aspiring to address the unmet medical needs of patients with cancer through paradigm-shifting therapeutics, today reported that the first patient has been dosed in the Phase 1 trial evaluating VIP943 in patients with relapsed/refractory acute myeloid leukemia (R/R AML), myelodysplastic syndrome (MDS), and B-cell acute lymphoblastic leukemia (B-cell ALL), NCT06034275. "Dosing of the first patient is a major achievement for the VIP943 development program and our next-generation bioconjugation platform. This achievement occurred 17 business days from receiving our safe to proceed letter, underscoring the enthusiasm from our investigators and the strong execution capabilities of the Vincerx team," said Ahmed Hamdy, M.D., Chief Executive Officer of Vincerx. "VIP943 is the first ADC candidate from our pioneering bioconjugation platform, designed to address the challenges of current ADCs, by increasing the therapeutic index (ie, increasing efficacy and reducing toxicity). We are the first company to bring to the clinic a legumain-cleavable linker and the first to utilize a kinesin spindle protein inhibitor (KSPi) as an ADC payload. This innovative and proprietary combination has generated strong preclinical evidence of activity and safety and has the potential to shift the treatment paradigm for patients with CD123+ hematologic malignancies. We look forward to evaluating the potential of VIP943 and expect to report preliminary safety and pharmacology data from our Phase 1 study in 2024." Stephen A. Strickland, Jr., M.D., MSCI, Director of Leukemia Research for the Sarah Cannon Research Institute (SCRI) and Principal Investigator on the Phase 1 trial for VIP943, said, “Despite there being new medicines for hematologic malignancies such as AML, MDS and B-cell ALL, outcomes for many patients have not improved and relapse rates remain high. The urgent need for more effective treatment options persists. Several factors influence the outlook for these cancers including increased frequency in older patients and poor response rates, especially in patients who relapse after initial therapy. Vincerx’s preclinical data provides a strong rationale to support the evaluation of VIP943 in the setting of hematologic malignancies, with hopes of providing more effective and less toxic therapeutic options for patients.” Howard A. “Skip” Burris, III, M.D., President of SCRI and Scientific Advisory Board member for Vincerx, said, “There is growing hope for delivering targeted therapies through the use of ADCs. Targeting hematologic malignancies with an ADC that combines selective binding to CD123 and a potentially improved safety profile, compared to other ADCs and CD123-targeting therapies, could provide a much needed treatment option for patients. Our team is excited to collaborate with Vincerx and begin enrolling patients in this Phase 1 dose escalation study.” About VIP943 VIP943 is the lead program from our next-generation ADC platform. VIP943 binds to CD123, a validated target in myeloid malignancies. Once inside the cell, it is only cleaved by an intracellular protein called legumain, allowing specific release and activation of the KSPi payload within the cancer cell. KSPi provides a novel way to deliver a cell cycle arrest agent, leading to cell death, which is a clinically validated ADC payload class mechanism. Vincerx’s novel legumain-specific linker substantially reduces non-specific release of the payload, thereby reducing unwanted side effects on healthy cells. In addition, Vincerx’s CellTrapper™ technology ensures that the KSPi payload accumulates in the target cells, limiting uptake into non-target, non-dividing cells. The innovative and intentional combination of a validated CD123 antibody, an intracellular cleavable legumain linker, and a potent KSPi payload holds the potential to address prevalent challenges of many ADCs by increasing the therapeutic window, thus improving efficacy and reducing common, severe toxicities such as myelosuppression, infections, peripheral neuropathy, and hepatotoxicity. VIP943 has demonstrated increased survival and reduced tumor burden in AML cell lines and patient-derived tumor models. Additionally, Vincerx presented preclinical data on VIP943 at ASH 2022, demonstrating superiority versus Mylotarg™, an approved ADC, with significantly improved safety in monkeys and better efficacy in a mouse model of acute leukemia. Preclinical data suggest that VIP943 does not induce significant cytokine release syndrome, common to other CD123-targeting agents, and demonstrated favorable safety in monkeys, with an optimal drug metabolism and pharmacokinetics profile. The Phase 1 trial of VIP943 is intended to assess safety, pharmacokinetics/pharmacodynamics, and preliminary efficacy of VIP943 in patients with R/R AML, MDS and B-cell ALL. The study will be conducted in several prominent U.S. cancer centers. About Vincerx Pharma, Inc. Vincerx Pharma, Inc. 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 the next-generation antibody conjugate, VIP943, in Phase 1; small molecule drug-conjugate, VIP236, in Phase 1; preclinical antibody drug conjugate, VIP924; CDK9 inhibitor, enitociclib, currently in an NIH-sponsored Phase 1; and its next-generation modular bioconjugation platform. Vincerx is based in Palo Alto, California, and has a research facility in Monheim, Germany. For more information, please visit . Forward-Looking 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 Vincerx’s 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 and product development milestones; changes in the assumptions underlying Vincerx’s expectations regarding its future business or business model; Vincerx’s ability to successfully develop and commercialize product candidates; Vincerx’s capital requirements and availability and uses of capital; and the risks and uncertainties set forth in Form 10-Q for the quarter ended June 30, 2023 and other reports filed with the Securities and Exchange Commission 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 Joyce Lonergan LifeSci Advisors, LLC 781-528-5276 JLonergan@lifesciadvisors.com

近日，在AACR2023上，Vincerx Pharma展示了一款治疗淋巴瘤的CXCR5-ADC产品VIP924的临床前数据。CXCR5属于趋化因子家族，是GPCR靶点的其中一种。其家族成员中，全球仅有CXCR4有一款拮抗剂产品上市(plerixafor)。靶点本身的机制CXCR5本身在B细胞和滤泡辅助T细胞上显著表达。在肿瘤、自免和慢性炎症中，CXCR5主要通过CXCL13-CXCR5轴来进行信号传递。Biochimica et Biophysica Acta(BBA) - Reviews on Cancer促瘤：在肿瘤中，CXCL13-XCXR5能通过双重途径促进肿瘤进展和发生。▷ 直接作用。CXCR5作为G蛋白偶联受体，结合GDP，激活PI3K，通过诱导Raf/MEK/ERK途径、整合素β3粘附激酶(FAK)/Src-paxillin和DOCK2/Rac/JNK途径来调节肿瘤细胞侵袭、生长和迁移。▷ 通过TME免疫细胞影响免疫监视。趋化因子的基础作用即包括将免疫抑制细胞募集到肿瘤微环境中。▷ CXCL13-CXCR5轴通过诱导IL-10协助恶性肿瘤细胞逃避T效应细胞免疫。▷ CXCL13-CXCR5还参与MDSC和Treg细胞的募集，促进肿瘤细胞存活、血管生成和侵袭。抑瘤：▷ CXCL13将CXCR5 B细胞和CXCR5 Tfh细胞募集到肿瘤部位，从而形成肿瘤TLO，促进有效的抗原呈递、细胞活化和分化，启动和维持局部和全身抗肿瘤T细胞和B细胞反应。▷ CXCR5的存在与否则可能会影响CD8+ CTL的抗肿瘤活性。与CXCR5-CD8+ T细胞相比，CXCR5+CD8+ T细胞在不同肿瘤类型中的增殖能力、颗粒酶B生成、肿瘤坏死因子α和干扰素γ表达均增强，从而引起更有效的杀瘤作用。其转录与表征和未耗尽的效应记忆CD8+ T细胞一致，定位到B细胞滤泡，表明其功能特征类似于CD4+ T滤泡辅助细胞。▷ 此外，CXCL13-CXCR5轴还可以与免疫检查点连接，以增强抗肿瘤作用。▷ 在淋巴细胞血液瘤中，CXCL13-CXCR5轴介导B细胞和Tfh细胞的归巢，有利于淋巴组织的构建。例如在在DLBCL中，CXCR5CD4 T细胞通过STAT3和STAT1的磷酸化促进肿瘤细胞的存活和增殖，并分泌IL-10。作为靶点，靶向CXCL13的研究似乎相对更多些。Vincerx数据结构：VIP924由CXCR5单抗、legumain-可裂解linker和驱动蛋白纺锤体蛋白KSPi抑制剂组成。机制：在细胞内，VIP924在溶酶体内被legumain裂解，细胞毒性有效载荷在细胞浆内释放。当细胞分裂时，KSPi与其靶蛋白结合并抑制有效的纺锤体形成。KSPi上的细胞捕集器修饰是用于阻止KSPi扩散出细胞。据称与其他B细胞结合抗体相比，VIP924中的CXCR5抗体显示出出色的细胞内化能力，但未展示具体数据。与CD19、CD22、CD70和CD79b作为抗体靶点的KSPi-ADC对比，CXCR5在不同淋巴瘤中的细胞毒性水平：可以看到，在GC-DLBCL中较为突出但不如CD70，在BurkL中相对碾压，但是B-NHL、一般DLBCL和MCL中细胞毒性都不是较优的选择。安全性数据：剂量递增数据：对CXCR5高表达的LY2214动物模型随机给予VIP924 10 mg/kg第1、5天，第10、15、20天给予4 mg/kg VIP924，每周1次，共3周。两个治疗组都显示出主要的抗肿瘤活性。10mg/kg组和4mg/kg组的TGI分别为87%和91%(P<0.0001)。其中，在HBL-1异种移植瘤模型中，一次应用10mg/kg VIP924导致三只小鼠中有两只完全反应，没有留下可测量的肿瘤。小结Vincerx之前是做小分子抑制剂和小分子偶联药物的。进展最快的产品是CDK9抑制剂。ADC，一个热门但是又非常挑战创新技术的话题。对于一些药企来说，能够上这艘船也意味着更广阔的的应用领域。具体地对于Vincerx而言，能将偶联技术扩展到更热门的领域是管线拓展的一个可行方向。单看这一款产品，CXCR5的靶向性是足够的，但是CXCR家族这么久以来没有成药也是有显著的机制原因在，从理论上而言，ADC的结构能让其摆脱CXCR5复杂体内机制的困扰，不失为对此类有效但复杂的靶点的探索方式。选择这么难的靶点，不知道Vincerx是否有什么独家心得。目前从这次海报披露的数据来看，适应症的竞争不算小，同时，也没有显示对CXCR5抗体有什么进行工程化处理的考虑。不过两个剂量组的肿瘤抑制率(TGI)都很高，即使对于非最优靶点的适应症，也表现出了优秀的肿瘤杀伤能力。Vincerx探索ADC，感觉也像是一点行业的缩影，对这个赛道现在是“又爱又恨”。参考资料：1.https://investors.vincerx.com/static-files/87a84746-dd73-4502-b779-a3c74329e4402.Binhan Wang, Manni Wang,et al.CXCL13-CXCR5 axis: Regulation in inflammatory diseases and cancer,Biochimica et Biophysica Acta (BBA) - Reviews on Cancer,Volume 1877, Issue 5,2022,188799,ISSN 0304-419X,https://doi-org.libproxy1.nus.edu.sg/10.1016/j.bbcan.2022.188799.3.https://www.biospace.com/article/releases/vincerx-pharma-presents-preclinical-data-on-vip924-a-first-in-class-antibody-drug-conjugate-adc-at-the-2023-american-association-for-cancer-research-aacr-annual-meeting-/?s=86

VIP924, a first-in-class CXCR5-ADC showed significant activity in patient-derived (PDX) lymphoma mouse models PALO ALTO, CA, USA I April 19, 2023 I 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: 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 www.vincerx.com . SOURCE: Vincerx Pharma