Alnuctamab

Under CEO Boerner, BMS continues to peel back a string of deals made under former leader Caforio\'s leadership.\n Bristol Myers Squibb has terminated cell therapy pacts with two biotechs amid \"ongoing portfolio prioritization efforts” within the Big Pharma, one of the affected companies revealed in an SEC document.The cuts were disclosed in separate Securities and Exchange Commission (SEC) filings made by Century Therapeutics and Immatics.Philadelphia-based Century had entered a collaboration with BMS back in 2022 in which the partners were working to develop stem cell-derived, engineered natural killer cell and gamma delta T cell candidates for blood cancers. The Big Pharma paid out $150 million in cash and an equity investment, plus committed more than $3 billion in biobucks.Now, after reviewing its portfolio, BMS is terminating the entire deal “without cause,” according to an SEC document filed Dec. 12. The dissolution is effective March 12, 2025.The programs have stayed in discovery and early-preclinical stages, with Century “encouraged by the scientific progress on the programs,” according to the SEC document. The biotech, which is currently conducting a strategic review of its preclinical pipeline, said it will assess potential opportunities for the programs in acute myeloid leukemia and multiple myeloma.The termination is “disappointing, but okay,” analysts from Leerink Partners wrote in a Dec. 13 note. The BMS decision doesn’t change the analysts\' positive long-term view of Century’s cell therapy platform or lead program, a CD19-targeting autoimmune candidate in phase 1 testing, the Leerink team noted. Given the partial focus on multiple myeloma, the Leerink Partners team wrote that the termination may reflect BMS’ acknowledgement that competitive hurdles in the indication are too high to warrant significant investments in the space. Because of that, the Leerink analysts don\'t assume the termination indicates anything negative about Century’s platform.The reprioritization at the Big Pharma, while “unfortunate,” is consistent with recent pipeline decisions made under CEO Chris Boerner, Ph.D.—who replaced Giovanni Caforio, M.D., last year—that indicate “more judicious resource allocation on oncology assets,” Leerink\'s analysts wrote.Since Boerner has taken the reins, BMS has also dropped a deal related to Agenus’ TIGIT bispecific antibody and an agreement with Eisai for its antibody drug conjugate (ADC).German biotech Immatics can now be added to that list, too. BMS inked a deal related to Immatics’ T-cell engager development in 2022—an expansion of a 2019 pact that focused on an autologous T cell receptor-based therapy (TCR-T). The revised deal included multiple off-the-shelf TCR-T and CAR-T programs, plus an upfront payment of $60 million and the chance to make up to $700 million per program through milestone and royalty payments.In 2023, BMS expanded the deal once again, exercising an option on an unnamed TCR-T.The two pact expansions have now been discarded, effective March 12 of next year, according to Dec. 13 SEC documents. The initial 2019 agreement remains intact. Earlier this year, BMS also jettisoned a bispecific molecule it licensed from Immatics for $150 million upfront in late 2021.The Big Pharma has also discontinued two internal multiple myeloma programs this year, including a phase 3-ready BCMA bispecific called alnuctamab because the company’s “business objectives” changed and a latestage BCMA CAR-T due to slow patient enrollment. 

印度仿制药公司Glenmark Pharmaceuticals似乎相中了业内潜在最佳的三抗。 Glenmark Pharmaceuticals是1977年成立的印度老牌仿制药企，近年来正在寻求转型，其瑞士盟友Ichnos Sciences之前就与Glenmark Pharmaceuticals达成了合作联盟，建立了一家合资公司Ichnos Glenmark Innovation。  近日，Ichnos Sciences宣布，已在Nature Cancer发表关于该公司CD3/BCMA/CD38三抗ISB 2001的临床前数据。结果显示，ISB 2001比强生的teclistamab（CD3xBCMA双抗）更有效地缩小了小鼠的多发性骨髓瘤肿瘤，并杀死了人体组织中的癌细胞，引起的T细胞因子分泌更少，因此比现有多发性骨髓瘤双抗更有优势的治疗窗口。 现有疗法的弊端 近年来，BCMA双抗和BCMA-CAR-T已经改变了多发性骨髓瘤（MM）的治疗格局，但是现有疗法仍然存在一些弊端。特别是治疗过后的复发问题仍待解决。 比如说，单药使用后就存在TAA表达下调，抗原丢失等问题，这类现象在CD38单抗daratumumab和BCMA-CAR-T中都能够观察到。 靶标达异质性可能是导致问题的原因之一，一些低CD38/BCMA表达的异质性肿瘤就会在杀伤后扩增。一些MM细胞甚至会在BCMA-CAR-T治疗后发生BCMA阴性突变导致耐药性逐渐增加。 另外，缓解深度似乎也是复发的关键因素。早先的荟萃性研究就表明，杀死微小残留病（MRD）阴性肿瘤是MM治疗成功的保障。为了解决这些问题，多靶点策略或许是这些问题的最佳解决方案，近年来CD3xBCMA双抗teclistamab+CD38单抗daratumumab的组合就被提上日程。CD38单抗无法清除的MRD就可能有赖于CD3xBCMA双抗teclistamab，反之亦然。 相似的策略还有同时靶向BCMA和CD38的CAR-T。 目前来看，多药联用已经展现出了较为优异的临床数据，联合方案可以获得较高的初始ORR，值得期待或许OS和PFS数据的读出。 虽然如此，CRS（细胞因子综合征）问题一直是TCEs在人体内应用时的阻碍，尤其是当teclistamab+daratumumab共同应用时，更加应该担忧治疗窗口。患有严重或危及生命的CRS的患者需要重症监护，需要采取安全缓解措施。 三抗ISB 2001的对应优势 ISB 2001运用了Ichnos Sciences的BEAT平台（基于T细胞受体的抗体的双特异性接合）能够将T细胞表面蛋白CD3的结合位点连接到抗体重链上，重链上同时兼有BCMA结合位点，Y型的另外一边重链则能够靶向CD38。 相较于teclistamab+daratumumab的组合，ISB 2001在临床前的体外和体内数据都更为优异。 相比于BMS已经放弃的alnuctamab以及强生的teclistamab，ISB 2001具有20-260倍的杀癌效力。 为了进一步测试ISB 2001的杀癌能力，研究人员将人类骨髓瘤细胞移植到小鼠身上，并用抗体治疗。在0.1mg/kg的剂量下，ISB 2001完全根除了所有八只小鼠的肿瘤；同时，接受teclistamab治疗的小鼠没有完全消退，只达到了30.8%的肿瘤生长抑制。 而在CRS问题上，ISB 2001也具有一定潜在优势，虽然细胞毒性上，ISB 2001比teclistamab高10-100倍，但ISB 2001在体外诱导了相似的细胞因子分泌。 这表明T细胞活化和细胞溶解活性所需的TCR刺激浓度远低于CRS发生的阈值。这解释了为什么ISB 2001尽管细胞毒性高，但并未显著增加CRS的风险。 因此理论上来说，ISB 2001有更大的治疗窗口。 目前这家公司已经招募了20人的ISB 2001的I期临床，预计相关数据将在今年晚些时候发布。 对于Glenmark来说，或许更值得担心的是市场和工艺，就在上个月BMS放弃了CD3xBCMA双抗alnuctamab，原因是市场竞争，疗效更优的ISB 2001是否能凭借性价比杀入未来市场值得一看。 参考来源： Carretero-Iglesia, L., Hall, O.J., Berret, J. et al. ISB 2001 trispecific T cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells. Nat Cancer (2024). https://doi.org/10.1038/s43018-024-00821-1 https://iginnovate.com/2024/09/11/igi-announces-publication-in-nature-cancer-on-isb-2001-igis-innovative-trispecific-antibody-for-relapsed-refractory-multiple-myeloma/