CD96

Preclinical findings demonstrate superior pharmacological activity, offering a differentiated mechanism-of-action to enhance anti-tumor immunity in advanced solid cancers LEXINGTON, Mass.--(BUSINESS WIRE)-- Agenus Inc. (“Agenus”) (Nasdaq: AGEN), a leader in discovering and developing novel immunological agents to treat various cancers, today announced that the first preclinical data from BMS-986442 (AGEN1777) will be presented in an oral presentation at the upcoming AACR Meeting, to be held April 5 – 10, 2024 in San Diego, CA. In non-clinical assays, BMS-986442 demonstrated superior immune activation both as monotherapy and in combination with PD-(L)1 blockade compared to conventional TIGIT antibodies. This novel, Fc-enhanced, bispecific antibody is differentiated from conventional TIGIT monoclonal antibodies by optimally targeting two critical immune checkpoint receptors in the same pathway, TIGIT and CD96. BMS-986442 (AGEN1777) leverages Agenus’ proprietary Fc-engineering platform to harness novel mechanisms of action that extend beyond the capabilities of conventional anti-TIGIT therapy. This innovative strategy could represent a promising approach to overcome the limitations of current anti-TIGIT therapies. “Immune checkpoint blockade has emerged as a powerful strategy in enhancing anti-tumor immunity. However, conventional TIGIT antibodies have faced limitations with monotherapy activity in clinical settings,” said Dhan Chand, Ph.D., Vice President of Research. “BMS-986442 has the potential to address these challenges through Fc modification and the targeting of complementary pathways.” Presentation Details: Abstract Title: BMS-986442 (AGEN1777), a novel TIGIT/CD96 bispecific antibody, demonstrates superior monotherapy and combination activity versus conventional anti-TIGIT antibodies in preclinical models Abstract Number: 3915 Presenting Author: Dhan Chand Session: Immune Targets and Therapies Presentation Session Date and Time: Monday April 8, 2024, 2:30 p.m. – 4:30 p.m. PST Data presented at the conference will be available to view in the publications section of the Agenus website ( ) following the AACR Meeting. About BMS-986442 (AGEN1777) BMS-986442 (AGEN1777) is being developed in partnership between Agenus and Bristol Myers Squibb. The TIGIT and CD96 bispecific antibody is currently being investigated for the treatment of multiple solid tumors in clinical studies in combination with nivolumab and/or chemotherapy. TIGIT is expressed on T cells and NK cells, sharing ligands with the CD96 receptor, and generating co-stimulatory or co-inhibitory signals. Co-inhibition of TIGIT and CD96 is intended to restore effector cell function by blocking the inhibitory immune checkpoint signaling pathway. About Agenus Agenus is a leading immuno-oncology company targeting cancer and infectious diseases with a comprehensive pipeline of immunological agents. The company’s mission is to expand patient populations benefiting from cancer immunotherapy through combination approaches, using a broad repertoire of antibody therapeutics, adoptive cell therapies (through MiNK Therapeutics) and adjuvants (through SaponiQx). Agenus is headquartered in Lexington, MA. For more information, visit or @agenus_bio. Information that may be important to investors will be routinely posted on our website and social media channels. Forward Looking Statements This press release contains forward-looking statements that are made pursuant to the safe harbor provisions of the federal securities laws, including statements regarding a partnered BMS-986442 program, expected timelines, and any other statements containing the words "may," "believes," "expects," "anticipates," "hopes," "intends," "plans," "forecasts," "estimates," "will," “establish,” “potential,” “superiority,” “best in class,” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially. These risks and uncertainties include, among others, the factors described under the Risk Factors section of our most recent Quarterly Report on Form 10-Q or Annual Report on Form 10-K filed with the Securities and Exchange Commission. Agenus cautions investors not to place considerable reliance on the forward-looking statements contained in this release. These statements speak only as of the date of this press release, and Agenus undertakes no obligation to update or revise the statements, other than to the extent required by law. All forward-looking statements are expressly qualified in their entirety by this cautionary statement.

GSK CEO Emma Walmsley sees particular potential to outperform in specialty oncology. GSK is moving to ease worries about the looming loss of exclusivity on its HIV blockbuster, setting out plans to launch at least 12 major products and deliver more than 38 billion pounds sterling ($48 billion) in risk-adjusted sales by 2031. The company expects dolutegravir, which brought in (PDF) 5.4 billion pounds last year, to lose exclusivity in the U.S. and the EU from 2028 to 2030. With the HIV drug accounting for almost 20% of sales in 2023, the prospect of generic rivals turning a major product into a footnote in GSK’s earnings is a source of concern for investors as they evaluate how the company will look at the end of the decade. GSK used its fourth-quarter results to try to allay those concerns. Talking on GSK’s results call with investors, CEO Emma Walmsley set out a “planned set of near-term new product launches, each with peak year sales potential of 2 billion pounds or more,” that will soften the impact of the loss of exclusivity. The road map includes more than 4 billion in peak sales linked to both depemokimab, the long-acting anti-IL-5 treatment GSK is studying in asthma, and pneumococcal vaccines acquired in the $3.3 billion takeover of Affinivax. GSK tipped mRNA seasonal flu and combination sales to top out above 3 billion pounds and the cough candidate acquired in the $2 billion Bellus buyout to hit 2.5 billion pounds. GSK is predicting more than 38 billion pounds in 2031 sales. Walmsley said GSK recognizes “there is development risk” and, “by definition, not everything will come through.” But, equally, the forecast is risk-adjusted and, as such, “there’s significant potential for upside with successful development outcomes,” the CEO said.  Walmsley sees particular potential to outperform in specialty oncology, “reflecting the development risk and the upside returns.” The cancer side of the schedule features new opportunities for Jemperli, GSK’s PD-1 drug, and antibodies that target the CD226 axis. GSK has invested in all three CD226 checkpoints, namely TIGIT, CD96 and PVRIG, and believes the gamble may be rewarded with 2 billion pounds in peak sales. Tony Wood, Ph.D., chief scientific officer at GSK, told investors that data on the CD226 axis will “begin to mature” toward the end of the year and will support conversations about “exploring our combinations with TIGIT in particular.” Lung and head and neck cancer are among the indications on GSK’s hit list.

*仅供医学专业人士阅读参考肿瘤微环境（TME）真是个神秘的地方。TME能为癌细胞提供合适的生长环境，还阻挡免疫细胞的进攻，即使精锐免疫细胞突破重围闯进TME，也会在种种“诱惑”之下丧失战意、忘记抗癌本职。TME，太可怕了。近期，伯明翰大学科学团队在《自然·通讯》杂志发文，研究者们发现，肿瘤特异性自然杀伤（NK）细胞竟然在进入TME 24小时后就迅速失去抗肿瘤效应功能、表现出独特的组织驻留表型，不再积极地促进抗肿瘤反应。TME是什么可怕的温柔乡啊。好在，研究者也发现，IL-15能够再度唤醒NK细胞的战意，令其恢复抗肿瘤功效。论文题图随着免疫疗法的兴起，人们对肿瘤内免疫细胞的兴趣也越来越浓厚，其中最受关注的自然是细胞毒性CD8+T细胞。不过也别忘了NK细胞，其实NK细胞也有强大的细胞毒性，它能够释放一系列颗粒酶和穿孔素，具有多种诱导细胞凋亡的配体；除了直接的细胞毒性功能，它也可以产生各种趋化因子，与树突状细胞（DC）配合，协调T细胞的工作。可以说，在抗癌方面，NK细胞真是又能辅助又能C。这么优秀的抗癌战士，癌细胞绝不会忽视。有研究发现，肿瘤内的NK细胞存在表型异质性和功能障碍，这可能会影响NK细胞的抗癌效果。NK细胞进入肿瘤后到底发生了什么？今天要介绍的这项研究想要搞清楚的就是这个问题。研究者们选用了一种独特的转基因动物模型，Kaede光转换小鼠，这种小鼠全身表达绿色的荧光蛋白，且在暴露于紫外光后不可逆地变为红色荧光。通过操纵光暴露，就能够通过荧光标签来标记进入肿瘤后不同时间的NK细胞了。研究者首先给小鼠皮下移植了MC38结肠癌细胞，并在光照后2天采样，分析细胞表型并进行scRNA测序。分析结果显示，进入肿瘤后，NK细胞的表型发生了显著的变化，最为明显的是CD11b和CD49a两个表面标记，进入肿瘤后的NK细胞逐渐丢失了CD11b、但出现了CD49a表达。CD11b是循环中成熟NK细胞的标志，而CD49a则是组织驻留NK细胞的标志。进入肿瘤后NK表达CD49a对基因表达的分析也发现，NK细胞进入肿瘤后，Pdcd1、Lag3、Havcr2、Cd96等抑制性受体表达上调，与DC募集相关的趋化因子Ccl3、Ccl4、Ccl5等表达缺失，颗粒酶表达改变。基因富集分析显示，NK活化、脱颗粒、细胞毒性等相关途径都随着时间的推移减少。更详细地追踪NK细胞的命运，研究者发现，进入肿瘤5小时后，NK细胞群中还不存在CD49a+细胞，但在24小时后，已经有10%的NK细胞开始表达CD49a，等到72小时后，NK细胞已经基本全都是CD49a+细胞了。NK细胞趋化因子等表达变化进入肿瘤后的NK细胞，简直是光速地失去了抗癌能力。研究者发现，瘤内NK细胞已经失去了CCL5的表达，IFNγ表达水平显著低于脾内NK细胞，颗粒酶A表达降低，颗粒酶C表达升高，穿孔素产生减少。体外实验显示，瘤内NK细胞的癌细胞杀伤能力显著下降。当研究者尝试寻找，是TME中的什么物质让NK细胞丧失战意，却没能得到一个具体的答案。TME中的TGFβ、PGE2通路、缺氧环境等条件，似乎都参与NK细胞的改变，似乎是TME整体营造出的“温柔乡”氛围让NK细胞丢盔卸甲。即使使用相应抗体耗竭瘤内NK细胞，也对肿瘤生长一点儿影响都没有。看来这些NK细胞是真没啥用了。好在，找不到具体的靶点并不意味着我们束手无策。IL-15有驱动T细胞和NK细胞分化和活化的能力，研究者使用活性更强的IL-15/IL-15Ra混合物处理荷瘤小鼠，显著延缓了肿瘤生长。进一步分析显示，IL-15令CD49a+NK细胞的抗肿瘤功能恢复了。IL-15显著改善肿瘤控制研究者还分析了521例人类结直肠癌样本，发现其中的NK细胞也表达出一种静止的非活化状态。对其进行表型分析，同样观察到了CD49a的表达和效应功能的丧失。这说明在人类中，上述使NK细胞失能的机制同样存在。回到开头的那句话，TME不仅神秘还特别危险，连NK细胞都一入TME深似海、从此抗癌不记得了，幸好它还没彻底报废，来点IL-15，又是一条好汉啦！参考资料：[1]https://www-nature-com.libproxy1.nus.edu.sg/articles/s41467-024-44789-z本文作者丨代丝雨