Mecbotamab vedotin

关注小药说药，一起成长！ 前言 抗体药物偶联物（ADC）疗法近几十年来发展迅速，目前全球已有16种产品获得批准，140多种ADC正在临床试验中。到2030年，ADC市场将达到150亿美元以上。ADC的基本原理：通过将单克隆抗体的特异性与有效小分子药物的细胞毒性相结合，ADC可以精确地向肿瘤输送毒素，同时保留正常组织，增加药物的治疗窗口。 临床前数据表明，将药物与抗体偶联可降低药物的最小有效剂量（MED）并增加药物的最大耐受剂量（MTD）。但越来越多的临床证据表明，ADC的耐受剂量与相关小分子的耐受剂量没有显著差异。在细胞毒素含量标准化后，ADC和人体中相应小分子的MTD大致相同。因此，目前人们对于ADC治疗窗口的一般理解可能是是不准确的。这里我们探讨关于ADC治疗窗口的几个问题，希望能够提供一些助益，有助于改进下一代ADC的设计。 ADC真的能实现比小分子更高的MTD吗？ 药物的MTD是没有严重副作用（剂量限制性毒性）的最高耐受剂量。过去，确定MTD是第一阶段肿瘤试验的主要目标。最近，特别是对于新的靶向药物（包括ADC），重点放在确定推荐的2期剂量（RP2D），它能更好地观察多个治疗周期后出现的慢性毒性和某些2级副作用。 上图总结了10个已批准ADC药物的MTD/RP2D值，通过将ADC和小分子剂量转换为共同单位后，可以标准化分子量和药物抗体比，更准确地比较ADC与有效载荷小分子的治疗窗口。结果很明显，ADC并没有显著提高其有效载荷的MTD，这一认识可能有助于深入了解该领域的几个现有的观察结果： （1） 具有共同有效载荷-连接子的ADC通常会遇到类似的MTD，因为有效载荷相关的平台毒性，与靶抗原无关。这突出表明，大多数非靶向不良事件与抗体无关。 （2） 正常组织中抗体靶向结合产生的靶向非肿瘤毒性是比较常见的。在这种情况下，MTD可能低于使用相同有效载荷-连接子的其他ADC。例如，Dato DXd（靶向TROP2的DAR4 DXd ADC）未能达到与其他含有DXd的ADC（T-DXd、HER3-DXd、B7H3-DXd和CDH6-DXd）相同的细胞毒素剂量，这可能是由于与正常组织中TROP2表达引起的药物相关不良事件（皮疹、口炎和粘膜炎）。在用其他TROP2 ADC治疗的患者中也观察到对皮肤和口腔粘膜的类似毒性。 （3） 通过设计限制与正常组织结合的工程化ADC（例如，CX-2009、CX-2029、BA3011、BA3021）与具有相同有效载荷-连接子的常规ADC相比，并没有改善MTD。 （4） 在一些情况下，降低ADC的DAR会导致耐受ADC剂量的成比例增加，但在细胞毒素量标准化后几乎没有改善。例如，与其他DAR4 MMAE ADC相比，ALT-P7（DAR2 MMAE ADC）具有类似的MTD。相应地，B7H3 DXd（DAR4）与其他DAR8 DXd ADC没有区别。 虽然有点令人惊讶，ADC之前被广泛地认为可以拓宽其有效载荷的治疗窗口，但从临床数据可以清楚地看出，MTD没有增加。这也得到了近40个活跃ADC的临床数据的证实。 为什么有效载荷和ADC的MTD没有显著变化？ ADC未能提高其有效载荷MTD的原因仍不明确。一种可能的解释在于抗体在保护有效载荷免受清除和代谢中所起的关键作用。有效载荷“全剂量”附着在抗体上，直到ADC靶向和非靶向介导的细胞摄取并分解代谢释放自由有效载荷或有效载荷代谢物，而这些代谢物又通过传统的小分子途径被清除。 ADC有效载荷-连接子也可以在血浆或肿瘤微环境中进行细胞外裂解，从而在循环中提供有效载荷的直接来源，而无需内吞。虽然较新的ADC使用比前几代更稳定的连接子，但一些有效的ADC（包括批准的ADC）是使用在血浆中半衰期相对较短的连接子构建的。 此外，通过硫醇马来酰亚胺化学制备的ADC，包括目前批准或正在开发的大多数ADC，可以使整个有效载荷-连接子从抗体中解偶联，这一过程称为逆Michael反应。例如，T-DXd和其他deruxtecan ADC、vedotin ADC以及许多正在开发中的ADC。对于这些ADC，高达50%-75%的有效载荷-连接子在大约7天后被解偶联，解偶联有效载荷-连接子迅速与含硫醇的血浆分子（主要是白蛋白）反应，形成新的偶联物。白蛋白在人类中有很长的半衰期，因此，有效载荷不会立即释放到循环中，而是保持在血液中，直到白蛋白结合物被分解。有效载荷-连接子从ADC转移到白蛋白这个过程可能通过白蛋白偶联物的非特异性沉积和增加有效载荷半衰期而产生某些毒性。另一方面，它也可能通过白蛋白偶联物直接被肿瘤吸收从而有助于抗肿瘤效果。然而，由于临床前模型中白蛋白的生物学特性与人的非常不同，因此对白蛋白在有效载荷-连接子解偶联相关的毒性和功效中作用的评估仍然难以实现。 ADC的疗效是否比其有效载荷有所提高？ 迄今为止批准的14个ADC证明了ADC治疗方法的重要性，DESTINY-Breast03和DESTINY-Breast04的最新数据突出了T-DXd改变乳腺癌治疗模式的潜力。另一方面，100多个终止的ADC项目也显示了选择抗体、靶点、有效载荷-连接子、DAR和适应症的正确组合的挑战。 在20世纪70年代，FDA癌症药物批准主要基于客观反应率（ORR），但从20世纪80年代初起，批准基于更直接的临床疗效证据，包括无进展生存率（PFS）和总生存率（OS）的改善。因为ORR直接归因于药物效应，ORR也是支持FDA加速批准的最常见的替代终点。考虑到ORR通常被用作早期ADC试验的主要终点，这里比较了用于治疗类似患者群体时小分子和ADC的ORR。 到目前为止，还没有直接的头对头随机临床试验将ADC与其有效载荷进行比较。最接近的例子是DESTINY-Gastric01试验中的T-DXd在医生选择的组中使用伊立替康（与DXd相同药物类别的拓扑异构酶I抑制剂）治疗：T-DXd治疗组的ORR为42%，而医生选择组为12.5%。有足够的临床数据可以得出结论，多个ADC显示出比相关小分子疗法更好的ORR。 哪些机制有助于ADC的成功？ 小分子的药代动力学（PK）通过与抗体偶联而发生根本性改变。ADC延长了细胞毒素的半衰期，包括保护其免受肾脏清除。另一方面，ADC面临着与其他生物制剂类似的问题，这些包括显著的非肿瘤靶向摄取和非特异性清除，毛细血管壁有限的外渗，由于肿瘤间质流体压力增加而导致肿瘤内低扩散，以及“结合位点屏障”现象（抗体结合到其靶点的速度快于其扩散速度，阻止了更深的渗透）。对于单克隆抗体，这些障碍中的一些可以通过增加剂量来克服，但这种策略不适用于ADC，因为偶联的细胞毒素决定了MTD。事实上，据报道，只有不到1%的ADC到达人体肿瘤，其余的ADC可能会造成不必要的毒性。因此，单用ADC肿瘤靶向可能无法解释相对于相关小分子的疗效提高。 因此，ADC可能依赖于其他机制来提高效率，例如有效地延长了循环中有效载荷的释放。抗原表达和ADC特性影响ADC PK和分解代谢，调节有效载荷释放的速率和位置，进而影响游离有效载荷的血浆水平和肿瘤局部浓度。其中，有效载荷旁观者活性的程度、偶联化学和连接子类型是关键的设计参数。 此外，来自不同肿瘤抗原表达水平患者的近期临床结果支持了循环有效载荷可产生基线抗肿瘤效应的观点。例如，许多ADC在肿瘤抗原低表达或阴性的患者中显示出疗效。抗体部分可提高由游离细胞毒素提供的基线活性效力，特别是在抗原高表达的肿瘤中。 通过比较脑转移的HER2+乳腺癌患者中trastuzumab、T-DM1和T-DXd的试验数据发现，在DESTINY-Breast03的亚组分析中，T-DXd和T-DM1的颅内ORR分别为64%和33%，而在单独试验中，trastuzumab没有产生客观反应。完整的血脑屏障（BBB）可阻止抗体渗透，但不会限制小分子，这取决于它们的物理化学性质。与trastuzumab相比，T-DXd（易渗透）和T-DM1（不易渗透）的循环中细胞毒性分解代谢物的倾向性可能为观察到的抗脑转移活性差异提供最佳解释。 小结 ADC的成功证明了将正确的靶点、抗体、偶联方式、DAR、连接子、有效载荷和疾病适应症结合起来可以产生显著的临床效益。然而，尽管存在广泛的多样性，目前的ADC并没有显著增加其有效载荷在多种肿瘤疾病状态下的MTD。因此， 更好地理解临床活性ADC的作用机制，例如抗体靶向递送、循环中持续的游离药物浓度、白蛋白转移或多种机制的组合、以及ADC结构成分及其PK/PD之间的相互关系对于设计下一代ADC非常重要。 参考文献： 1.The therapeutic window of antibody drug conjugates: A dogma in need of revision. Cancer Cell.2022 Oct 10;S1535-6108(22)00445-7 公众号内回复“ADC”或扫描下方图片中的二维码免费下载《抗体偶联药物：从基础到临床》的PDF格式电子书！ 公众号已建立“小药说药专业交流群”微信行业交流群以及读者交流群，扫描下方小编二维码加入，入行业群请主动告知姓名、工作单位和职务。

SAN DIEGO, Dec. 20, 2024 (GLOBE NEWSWIRE) -- BioAtla, Inc. (Nasdaq: BCAB), a global clinical-stage biotechnology company (“BioAtla” or the “Company”) focused on the development of Conditionally Active Biologic (CAB) antibody therapeutics for the treatment of solid tumors, today announced that it has entered into definitive agreements with certain institutional investors for the issuance and sale of 9,679,158 shares of its common stock in a registered direct offering. Each share of common stock offered was sold with a warrant to purchase one share of common stock at an exercise price of $1.19 per share. Each warrant will be exercisable beginning six months after issuance and will expire 5.5 years from the date of issuance. The combined offering price per share of common stock and accompanying warrant is $0.9520. The closing of the offering is expected to occur on or about December 20, 2024, subject to the satisfaction of customary closing conditions. The gross proceeds to the Company from the offering are expected to be approximately $9.2 million, before deducting expenses related to the offering payable by the Company. The Company intends to use the net proceeds to be received by it in the offering, along with its existing cash and cash equivalents, to fund its research and development efforts, including to reach several key inflection points for its mid-stage clinical T-Cell Engager (TCE) and Antibody Drug Conjugate (ADC) programs: BA3182 (CAB-EpCAM x CAB-CD3 TCE) Phase 1 dose escalation data (expected readout 2Q25) and Phase 2 expansion data (expected readout 1H26); and mecbotamab vedotin (CAB-AXL-ADC) Phase 2B data in mutated KRAS (mKRAS) non-small cell lung cancer (NSCLC) (expected readout 1H26), to support its partnering activities, and for working capital and other general corporate purposes. Tungsten Advisors (through its Broker-Dealer, Finalis Securities LLC) acted as the sole placement agent for the offering. The securities are being offered by the Company pursuant to an effective shelf registration statement on Form S-3 (File No. 333-262528) that was declared effective by the U.S. Securities and Exchange Commission (“SEC”) on May 18, 2022. The offering is being made only by means of a prospectus and related prospectus supplement. A prospectus supplement relating to and describing the terms of the offering will be filed with the SEC and will be available on the SEC's website at www.sec.gov. When available, electronic copies of the prospectus supplement and the accompanying prospectus may also be obtained from Tungsten Advisors (through its Broker-Dealer, Finalis Securities LLC), 767 Third Ave, 29th Floor, New York, NY 10017, by phone at (917) 268-1097 or email at prospectus@tungstenadv.com. This press release shall not constitute an offer to sell or the solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of any such state or other jurisdiction. About BioAtla®, Inc. BioAtla is a global clinical-stage biotechnology company with operations in San Diego, California, and in Beijing, China through its contractual relationship with BioDuro-Sundia, a provider of preclinical development services. Utilizing its proprietary CAB technology, BioAtla develops novel, reversibly active monoclonal and bispecific antibodies and other protein therapeutic product candidates. CAB product candidates are designed to have more selective targeting, greater efficacy with lower toxicity, and more cost-efficient and predictable manufacturing than traditional antibodies. BioAtla has extensive and worldwide patent coverage for its CAB technology and products with greater than 780 active patent matters, more than 500 of which are issued patents. Broad patent coverage in all major markets include methods of making, screening and manufacturing CAB product candidates in a wide range of formats and composition of matter coverage for specific products. BioAtla has two first-in-class CAB programs currently in Phase 2 clinical testing, mecbotamab vedotin, a novel conditionally active AXL-targeted antibody-drug conjugate (CAB-AXL-ADC), and ozuriftamab vedotin, a novel conditionally active ROR2-targeted antibody-drug conjugate (CAB-ROR2-ADC). The Phase 2 stage CAB-CTLA-4 antibody, evalstotug, is a novel CTLA-4 inhibitor designed to reduce systemic toxicity and potentially enable safer combination therapies with checkpoint inhibitors such as anti-PD-1 antibody. The Company’s first dual CAB bispecific T-cell engager antibody, BA3182, is currently in Phase 1 development. BA3182 targets EpCAM, which is highly and frequently expressed on many adenocarcinomas while engaging human CD3 expressing T cells. In the fall of 2024, the company out licensed its pre-clinical lead stage CAB-Nectin4 x CAB-CD3 TCE program for $15 million in upfront and near-term payments with another $118.5 million in milestones, plus double-digit royalties. To learn more about BioAtla, Inc. visit www.bioatla.com. Forward-looking StatementsThis press release contains forward-looking statements under the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995, including statements regarding the expected gross proceeds from the offering, the timing and completion of the offering, the anticipated use of proceeds therefrom, whether it will reach key inflection points in its programs and expected timing of data readouts. Any statements that are not statements of historical fact (including statements containing the words “believes,” “plans,” “could,” “anticipates,” “expects,” “estimates,” “should,” “target,” “will,” “would” and similar expressions) should also be considered to be forward-looking statements. Forward-looking statements are based on BioAtla's current expectations and are subject to inherent uncertainties, risks and assumptions, many of which are beyond its control, difficult to predict and could cause actual results to differ materially from what we expect. Further, certain forward-looking statements are based on assumptions as to future events that may not prove to be accurate. Factors that could cause actual results to differ include, among others: potential delays in clinical and preclinical trials; the uncertainties inherent in research and development, including the ability to meet anticipated clinical endpoints, commencement and/or completion dates for clinical trials, regulatory submission dates, or regulatory approval dates, as well as the possibility of unfavorable new clinical data and further analyses of existing clinical data; whether regulatory authorities will be satisfied with the design of and results from the clinical studies or take favorable regulatory actions based on results from the clinical studies; its dependence on the success of its CAB technology platform; its ability to enroll patients in its ongoing and future clinical trials; the successful selection and prioritization of assets to focus development on selected product candidates and indications; its ability to form collaborations and partnerships with third parties and the success of such collaborations and partnerships; its reliance on third parties for the manufacture and supply of its product candidates for clinical trials; its reliance on third parties to conduct its clinical trials and some aspects of its research and preclinical testing; potential adverse impacts due to any resurgence of COVID-19 and its variants; and those other risks and uncertainties described in the section titled "Risk Factors" in its Annual Report on Form 10-K filed with the SEC on March 26, 2024, in its Quarterly Report on Form 10-Q filed with the SEC on May 14, 2024, August 8, 2024 and November 7, 2024 and its other reports as filed with the SEC. Forward-looking statements contained in this press release are made as of this date, and BioAtla undertakes no duty to update such information except as required under applicable laws. Internal Contact:Richard WaldronChief Financial OfficerBioAtla, Inc.rwaldron@bioatla.com858.356.8945 External Contact:Bruce MackleLifeSci Advisors, LLCbmackle@lifesciadvisors.com