COM-701

前言 免疫检查点抑制剂是癌症免疫治疗研究的一个重要里程碑。PD-1/PD-L1和CTLA-4抑制剂已成功获得监管部门批准，用于多种癌症类型的治疗。然而，依然有一些原发性或适应性耐药患者可能无法从肿瘤免疫治疗的整体治疗潜力中获益。因此，探索新的免疫检查点抑制剂的可用性变得越来越重要。 一种新兴的共抑制受体CD112R（PVRIG）常见于自然杀伤细胞（NK）和T细胞上表达。它与配体（CD112或PVRL2/nectin-2）结合，抑制T细胞和NK细胞对肿瘤细胞的反应强度。因此，CD112R被认为是一种新型的免疫检查点，在肿瘤免疫治疗中具有很高的潜力。CD112的高水平表达与大多数癌症患者的肿瘤进展和不良预后有关。目前，CD112R的抑制剂已经在癌症患者的临床试验中得到验证，CD112R可能是一个非常有前景的靶点。 CD112R的结构与表达 CD112R是属于脊髓灰质炎病毒受体（PVR）家族的共抑制受体，最初被称为PVR相关Ig结构域（PVRIG）。在人类，CD112R为一个36kD的单次跨膜蛋白，包含一个跨膜区、一个长的细胞内结构域和一个细胞外免疫球蛋白可变样（IgV）结构域。 在正常人外周血细胞中，CD112R基因在NK和T淋巴细胞中表达，但在单核细胞衍生的树突状细胞（DC）、中性粒细胞（CD66b+）、单核细胞（CD14+）和B细胞（CD19+）中不表达。大多数表达CD112R的T细胞是CD8+T细胞，主要是效应/记忆细胞。值得注意的是，CD8+和CD4+T细胞的激活会进一步上调了CD112R的表达。 CD112R表达发生在各种类型实体瘤的NK细胞、CD8+T细胞和CD4+T细胞中。高水平表达常出现在肾脏、卵巢、肺、前列腺和子宫内膜的肿瘤中。同样，CD112R在急性髓系白血病的T细胞和NK细胞中表达。 此外，CD112R表达与CD8+和CD4+TIL上的PD-1和TIGIT表达同时出现，这与耗竭的T细胞表型显著相关。此外，CD112R的表达也与NK细胞上的耗竭标记物的表达相伴，包括CD96、TIGIT、Tim-3和PD-1。 CD112的结构与表达 CD112也称为连接蛋白-2或PVR相关蛋白2（PVRL2），是连接蛋白家族的成员，与肿瘤血管生成、生长和转移相关。CD112包括一个具有三个Ig样结构域（两个IgC和一个远端IgV结构域）的胞外区域、一个细胞质尾部和一个跨膜区域。细胞质尾部有一个保守的afadin结合基序（Glu/Ala-X-Tyr-Val），可以与PDZ结构域结合，从而帮助连接蛋白连接到F-肌动蛋白。 研究表明，CD112主要定位于上皮细胞的粘附连接处，并在各种细胞中广泛表达，包括上皮细胞、内皮细胞、神经元和成纤维细胞。此外，CD112也出现在癌细胞和免疫细胞中，如单核细胞和DC细胞。 CD112/CD155共抑制网络 在共抑制途径中，PVR和PVR样家族的成员，包括CD112R、TIGIT、CD96、CD155、CD226和CD112，形成一个复杂的信号网络调节T细胞的激活。 网络中的配体可以通过与不同受体结合来调节淋巴细胞的活性，CD155可以与CD226、TIGIT和CD96相互作用，而CD112与CD226、TIGIT和CD112R相互作用。而它们之间的亲和力也截然不同。 不同的抑制性和共刺激性检查点受体可以相互调节。当CD8+T细胞被特异性抗原激活时，观察到CD112R与TIGIT的共表达。CD112R阻断可导致TIGIT的诱导表达，而阻断TIGIT或PD-1后，未观察到CD112R表达的变化。由于CD226和CD112R在CD112上有相同的结合位点，CD226与抑制性免疫检查点CD112R竞争结合CD112，以促进T细胞活化。因此，CD112R可显著抑制T细胞中CD112–CD226的相互作用。 在各种癌症中，TIGIT的表达与TIL上PD-1的表达同时显著增加。与健康人相比，癌症患者的TIGIT水平更高，CD226水平更低。一些抑制性受体，包括TIGIT、Tim-3、PD-1和LAG-3，与野生型小鼠的CD8+T细胞相比，在CD112R−/−的小鼠浸润CD8+T细胞上高表达。因此，CD112R与其他免疫受体及其相关配体之间的竞争或协同调节控制肿瘤微环境中的免疫细胞浸润和激活。 CD112R/CD112轴在肿瘤治疗中的作用 在人类中，CD112R的表达发生在多种肿瘤的T细胞和NK细胞上。已知CD112R/CD112轴阻碍T细胞的免疫功能。与癌症免疫治疗中众所周知的PD-1/PD-L1通路一样，新型的CD112R/CD112通路可能很快在肿瘤免疫治疗方面发挥作用。 CD112R-CD112通路在调节T细胞杀死肿瘤细胞的过程中起着至关重要的作用。研究发现，在黑色素瘤和结肠癌的CD112R缺陷小鼠模型中，肿瘤生长停止，肿瘤免疫细胞浸润增加，尤其是CD8+T细胞。此外，在结肠癌模型中，发现抗CD112R阻断抗体单独或与PD-L1抑制剂联合使用可改善抗肿瘤效果并抑制难治性肿瘤进展。 此外，阻断CD112R有助于NK细胞的抗肿瘤功效并抑制肿瘤生长。在体外，CD112R或TIGIT阻断剂可增加与乳腺癌细胞共培养的IFN-γ+NK细胞的数量。CD112R和TIGIT单克隆抗体联合使用可诱导IFN-γ+NK细胞的额外增加，并提高NK细胞的细胞毒性。CD112R阻断能有效抑制肿瘤生长并延长荷瘤小鼠的生存期，这与肿瘤浸润NK细胞的频率和细胞毒性潜能的增强有关。 COM701是一种针对PVRIG的“first-in-class”的单克隆抗体，正在对标准治疗无效的晚期或转移性实体恶性肿瘤患者中进行一期临床试验（NCT03667716）。近期结果显示，28例患者（16例单药治疗，12例与nivolumab联合治疗）的疾病控制率（DCR）为57%（16/28），没有CRs。在接受治疗超过15周的原发性腹膜癌患者中，单药治疗组有1例确诊PR。在联合治疗组中，另有1名患者获得了未经证实的PR，治疗超过34周。没有DLT报告，最常见的不良事件是1级和2级疲劳、皮疹、水肿和恶心。初步结果表明，这种疗法具有潜在益且没有明显的副作用。它不仅可以作为一种辅助治疗，还可以成为一种可行的替代性单独治疗。 小结 已有的数据表明，CD112R-CD112轴在调节T细胞和NK细胞肿瘤杀伤能力方面具有重要的作用。靶向CD112R/CD112轴在癌症免疫治疗中表现出极具前景的应用。临床结果表明，CD112R阻断剂不仅可以作为一种辅助治疗，还可能成为一种可行的替代性单独治疗。随着对CD112R/CD112介导的免疫反应调节研究的深入，将有助于针对癌症患者进行CD112R阻断剂的优化组合策略设计，为更多的癌症患者带来益处。 参考文献： 1.The CD112R/CD112 axis: a breakthrough in cancer immunotherapy. JExp Clin Cancer Res. 2021; 40: 285. 2. Hitting the complexity of the TIGIT-CD96-CD112R-CD226 axis fornext-generation cancer immunotherapy. BMB Rep. 2021 Jan 31; 54(1): 2–11. 推文用于传递知识，如因版权等有疑问，请于本文刊发30日内联系医药速览。 原创内容未经授权，禁止转载至其他平台。 有问题可发邮件至yong_wang@pku.edu.cn获取更多信息。 ©2021 医药速览 保留所有权利 往期链接 “小小疫苗”养成记 | 医药公司管线盘点  人人学懂免疫学 | 人人学懂免疫学（语音版）    综述文章解读 | 文献略读 | 医学科普 | 医药前沿笔记 PROTAC技术 | 抗体药物 | 抗体药物偶联-ADC 核酸疫苗 | CAR技术 | 化学生物学 温馨提示 医药速览公众号目前已经有近12个交流群（好学，有趣且奔波于医药圈人才聚集于此）。进群加作者微信（yiyaoxueshu666）或者扫描公众号二维码添加作者，备注“姓名/昵称-企业/高校-具体研究领域/专业”，此群仅为科研交流群，非诚勿扰。 简单操作即可星标⭐️医药速览，第一时间收到我们的推送 ①点击标题下方“医药速览”   ②至右上角“...”  ③点击“设为星标

Clinical data presented at SITC 2024 supports further development of COM701, potential first-in-class anti-PVRIG antibody On track to initiate a randomized adaptive platform trial of COM701 maintenance therapy in patients with platinum sensitive ovarian cancer, scheduled to start in Q2 2025 The first patient was dosed in Q1 2025 in the first in human Phase 1 solid tumor trial of GS-0321 (previously COM503), a potential first-in-class anti-IL18BP antibody licensed to Gilead Partner AstraZeneca reported promising rilvegostomig data in 2024, expanded the rilvegostomig program to seven Phase 3 trials across lung and gastrointestinal cancers and plans to share early data for rilvegostomig in combination with their ADCs in 2025 Solid financial position with cash runway expected to fund operations into 2027 HOLON, Israel, March 4, 2025 /PRNewswire/ -- Compugen Ltd. (Nasdaq: CGEN) (TASE: CGEN) a clinical-stage cancer immunotherapy company and a pioneer in computational target discovery, today reported financial results for the fourth quarter and full year 2024 and provided a corporate update. "I believe Compugen is well-positioned for growth, building on significant progress made in 2024 together with a diverse and innovative pipeline and with a strong focus on execution in 2025," said Anat Cohen-Dayag, Ph.D., President and CEO of Compugen. "The clinical data we presented at SITC 2024, consistent with previous data, support advancing our potential first-in-class anti-PVRIG, COM701, to be evaluated as a maintenance treatment option for patients with platinum sensitive ovarian cancer. We are on track to initiate an adaptive platform trial, which is scheduled to start with a randomized placebo controlled sub-trial evaluating single agent COM701 therapy in Q2 2025. This development path is supported by a strong clinical and biological rationale and has the potential to open the door to advance COM701 as a single agent and as a backbone to future drug combinations." Dr. Cohen-Dayag continued, "We are also encouraged by the promising rilvegostomig data presented by our partner, AstraZeneca, in 2024. Rilvegostomig is a PD-1/TIGIT bispecific antibody, the TIGIT component of which is derived from COM902. AstraZeneca is running seven Phase 3 trials with rilvegostomig across lung and gastrointestinal cancers and plans to share early data for rilvegostomig in combination with their ADCs in 2025. AstraZeneca's broad development strategy for rilvegostomig to replace existing PD-1/PD-L1 inhibitors represents a significant potential revenue source for Compugen as we may be eligible for both future milestone payments and mid-single digit tiered royalties on future sales. Dr. Cohen-Dayag added, "Our solid financial position with a cash runway expected to fund our operations into 2027 allows us to advance our innovative clinical and early-stage pipeline. This includes advancing the Phase 1 trial of GS-0321, a potential first-in-class anti-IL18BP licensed to Gilead, for which we received a $30 million milestone payment for achieving IND clearance in 2024. Additionally, it enables us to continue to leverage our AI/ML powered predictive computational discovery platform, UnigenTM, to accelerate our research efforts supporting our early pipeline. Our Unigen platform is validated by our multiple potential first-in-class and potential best-in-class clinical programs, as well as our partnerships with AstraZeneca and Gilead." Next Planned Milestones Q2 2025 – initiation of a randomized adaptive platform trial comparing COM701 maintenance therapy to placebo in total of 60 patients with relapsed platinum sensitive ovarian cancer 2025 – Compugen's partner, AstraZeneca, plans to share early data for rilvegostomig in combination with their ADCs H2 2026 – data from projected interim analysis of single agent COM701 sub-trial 1 as maintenance therapy in relapsed platinum sensitive ovarian cancer Fourth Quarter and Full Year 2024 Financial Highlights Cash: As of December 31, 2024, Compugen had approximately $103.3 million in cash, cash equivalents, short-term bank deposits and investment in marketable securities. The cash balance at the end of 2024 includes the receipt of the upfront payment of $60 million from Gilead for the licensing of GS-0321, the $30 million milestone payment from Gilead for IND clearance (both subject to a 15% withholding tax) and the $15 million milestone payments from AstraZeneca on dosing of the first patient in the first and second major indications for rilvegostomig Phase 3 trials. In January and February 2025, subsequent to the financial results for the year ended December 31, 2024, a total of approximately 3.96 million shares were sold through the Company's ATM facility contributing net proceeds of approximately $8.87 million (net of $274 thousand commission issuance expenses). Compugen expects that its current cash will be sufficient to fund its operating plans into 2027. The Company has no debt. Revenues: Compugen reported approximately $1.5 million in revenues for the fourth quarter of 2024 and $27.9 million in revenues for the year ended December 31, 2024, compared to approximately $33.5 million in revenues for each of the comparable periods in 2023. The revenues for 2024 include the portion of the upfront payment and the IND milestone payment from the license agreement with Gilead and the $5 million clinical milestone payment from AstraZeneca, while the revenues for 2023 reflect the portion of the upfront payment from the license agreement with Gilead allocated to the license and the previous clinical milestone from the license agreement with AstraZeneca in the amount of $10 million. Cost of Revenues for the fourth quarter and year ended December 31, 2024, were approximately $0.7 million and $7.9 million, respectively, compared with approximately $2.0 million for both comparable periods in 2023. Cost of revenues for 2024 represents the cost of IND and Phase 1 activities and royalty payments in connection with Compugen's revenues, offset by royalty reversal in 2024 due to exemption received from the Israeli Innovation Authority from the requirement to pay royalties on income derived from sales associated with products related to IL-18BP, while cost of revenues for 2023 represents milestone and royalty payments in connection with our revenues. R&D expenses for the fourth quarter and year ended December 31, 2024, decreased to approximately $5.9 million, and $24.8 million, respectively, compared with approximately $10.9 million and $34.5 million for the comparable periods in 2023, respectively. The decrease in 2024 was mainly due to the classification of expenses related to GS-0321 to cost of revenues and to lower CMC and IND enabling activities related to GS-0321, partially offset by an increase in clinical expenses. G&A expenses for the fourth quarter and year ended December 31, 2024, were approximately $2.2 million and $9.4 million, respectively, compared with approximately $2.5 million and $9.7 million for the comparable periods in 2023, respectively. Net Income / Loss: During the fourth quarter of 2024, Compugen reported a net loss of approximately $6.1 million, or approximately 7 cents per basic and diluted share, compared to a net income of approximately $9.7 million, or approximately 11 cents per basic and diluted share in the comparable period of 2023. Net loss for the year ended December 31, 2024, was approximately $14.2 million, or approximately 16 cents per basic and diluted share, compared with a net loss of approximately $18.8 million, or approximately 21 cents per basic and diluted share in the comparable period in 2023. Full financial tables are included below. Conference Call and Webcast Information The Company will hold a conference call today, March 4, 2025, at 8:30 AM ET to review its fourth quarter and full year 2024 results. To access the conference call by telephone, please dial 1-866-744-5399 from the United States, or +972-3-918-0644 internationally. The call will also be available via live webcast through Compugen's website, located at the following link. Following the live audio webcast, a replay will be available on the Company's website. About Compugen Compugen is a clinical-stage therapeutic discovery and development company utilizing its broadly applicable predictive computational discovery platform (UnigenTM) to identify new drug targets and biological pathways for developing cancer immunotherapies. Compugen has two proprietary product candidates in Phase 1 development: COM701, a potential first-in-class anti-PVRIG antibody and COM902, a potential best-in-class antibody targeting TIGIT for the treatment of solid tumors. Rilvegostomig, a PD-1/TIGIT bispecific antibody where the TIGIT component is derived from Compugen's clinical stage anti-TIGIT antibody, COM902, is in Phase 3 development by AstraZeneca through a license agreement for the development of bispecific and multispecific antibodies. GS-0321 (previously COM503), a potential first-in-class, high affinity anti-IL-18 binding protein antibody, which is in Phase 1 development is licensed to Gilead. In addition, the Company's therapeutic pipeline of early-stage immuno-oncology programs consists of research programs aiming to address various mechanisms to enhance anti-cancer immunity. Compugen is headquartered in Israel, with offices in San Francisco, CA. Compugen's shares are listed on Nasdaq and the Tel Aviv Stock Exchange under the ticker symbol CGEN. Forward-Looking Statement To be updated This press release contains "forward-looking statements" within the meaning of the Securities Act of 1933 and the Securities Exchange Act of 1934, as amended, and the safe-harbor provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements are based on the current beliefs, expectations, and assumptions of Compugen. Forward-looking statements can be identified using terminology such as "will," "may," "expects," "anticipates," "believes," "potential," "plan," "goal," "estimate," "likely," "should," "confident," and "intends," and similar expressions that are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Forward-looking statements include, but are not limited to, statement regarding our expectations regarding the advancements of COM701 as a single agent and as a backbone to future drug combinations; statements regarding the initiation of a randomized adaptive platform trial comparing COM701 maintenance therapy to placebo in total of 60 patients with relapsed platinum sensitive ovarian cancer as well as the timing of any interim results from such sub-trial; statements regarding the timing of any data announcement by AstraZeneca regarding the combination of rilvegostomig with their ADCs; statements to the effect that our cash and cash-related balances will be sufficient to fund our operating plans into 2027; and statements that our cash position will enable us to continue to leverage our AI/ML powered predictive computational discovery platform, Unigen, to accelerate our research efforts supporting our early pipeline. These forward-looking statements involve known and unknown risks and uncertainties that may cause the actual results, performance, or achievements of Compugen to be materially different from any future results, performance or achievements expressed or implied by such forward-looking statements. Among these risks: the clinical trials of any product candidates that Compugen, or any current or future collaborators, may develop may fail to satisfactorily demonstrate safety and efficacy to the FDA, and Compugen, or any collaborators, may incur additional costs or experience delays in completing, or ultimately be unable to complete, the development and commercialization of these product candidates; Compugen's business model is substantially dependent on entering into collaboration agreements with third parties and Compugen may not be successful in generating adequate revenues or commercializing aspects of its business model; Compugen's approach to the discovery of therapeutic products is based on its proprietary computational target discovery infrastructure, which is unproven clinically; general market, political and economic conditions in the countries in which Compugen operates, including Israel; the effect of the evolving nature of the recent war in Israel; and Compugen does not know whether it will be able to discover and develop additional potential product candidates or products of commercial value. These risks and other risks are more fully discussed in the "Risk Factors" section of Compugen's most recent Annual Report on Form 20-F as filed with the Securities and Exchange Commission (SEC) as well as other documents that may be subsequently filed by Compugen from time to time with the SEC. In addition, any forward-looking statements represent Compugen's views only as of the date of this release and should not be relied upon as representing its views as of any subsequent date. Compugen does not assume any obligation to update any forward-looking statements unless required by law. Company contact: Yvonne Naughton, Ph.D. Head of Investor Relations and Corporate Communications Email: [email protected] Tel: +1 (628) 241-0071 SOURCE Compugen Ltd. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED