CLN-617 Retains IL2 and IL12 in Injected Tumors to Drive Robust and Systemic Immune-Mediated Antitumor Activity.

IF 8.1 1区 医学 Q1 IMMUNOLOGY
Naveen K Mehta, Kavya Rakhra, Kristan A Meetze, Bochong Li, Noor Momin, Jason Y H Chang, K Dane Wittrup, Patrick A Baeuerle, Jennifer S Michaelson
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Abstract

Despite clinical evidence of antitumor activity, the development of cytokine therapies has been hampered by a narrow therapeutic window and limited response rates. Two cytokines of high interest for clinical development are interleukin 2 (IL2) and interleukin 12 (IL12), which potently synergize to promote the activation and proliferation of T cells and NK cells. However, the only approved human IL2 therapy, Proleukin, is rarely used in the clinic due to systemic toxicities, and no IL12 product has been approved to date due to severe dose-limiting toxicities. Here, we describe CLN-617, a first-in-class therapeutic for intratumoral (IT) injection that co-delivers IL2 and IL12 on a single molecule in a safe and effective manner. CLN-617 is a single-chain fusion protein comprised of IL2, leukocyte-associated immunoglobulin-like receptor 2 (LAIR2), human serum albumin (HSA), and IL12. LAIR2 and HSA function to retain CLN-617 in the treated tumor by binding collagen and increasing molecular weight, respectively. We found that IT administration of a murine surrogate of CLN-617, mCLN-617, eradicated established treated and untreated tumors in syngeneic models, significantly improved response to anti-PD1 checkpoint therapy, and generated a robust abscopal response dependent on cellular immunity and antigen cross-presentation. CLN-617 is being evaluated in a clinical trial in patients with advanced solid tumors (NCT06035744).

CLN-617 可在注射的肿瘤中保留 IL-2 和 IL-12,从而产生强大的全身免疫介导抗肿瘤活性。
尽管有临床证据表明细胞因子具有抗肿瘤活性,但由于治疗窗口狭窄和反应率有限,细胞因子疗法的发展一直受到阻碍。白细胞介素 2(IL-2)和白细胞介素 12(IL-12)是临床开发中备受关注的两种细胞因子,它们能有效协同促进 T 细胞和自然杀伤(NK)细胞的活化和增殖。然而,由于存在全身毒性,唯一获批的人类 IL-2 疗法 Proleukin 很少用于临床,而由于存在严重的剂量限制毒性,迄今为止还没有 IL-12 产品获批。在此,我们介绍了CLN-617,它是第一种用于瘤内注射(IT)的同类疗法,能以安全有效的方式将IL-2和IL-12合二为一。CLN-617是一种单链融合蛋白,由IL-2、白细胞相关免疫球蛋白样受体2(LAIR2)、人血清白蛋白(HSA)和IL-12组成。LAIR2 和 HSA 的功能分别是通过结合胶原蛋白和增加分子量将 CLN-617 保留在治疗的肿瘤中。我们发现,IT给药的CLN-617小鼠替代物mCLN-617能根除在共生模型中已治疗和未治疗的肿瘤,显著改善对抗PD1检查点疗法的反应,并产生依赖于细胞免疫和抗原交叉呈递的强有力的脱落反应。CLN-617正在晚期实体瘤患者的临床试验中进行评估(NCT06035744)。
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来源期刊
Cancer immunology research
Cancer immunology research ONCOLOGY-IMMUNOLOGY
CiteScore
15.60
自引率
1.00%
发文量
260
期刊介绍: Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes. Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.
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