Whalen Kerry A, Henry Catherine C, Mehta Naveen K, Rakhra Kavya, Yalcin Safak, Meetze Kristan, Gibson Neil W, Baeuerle Patrick A, Michaelson Jennifer S
Cullinan Therapeutics Inc, Cambridge, Massachusetts, USA
Cullinan Therapeutics Inc, Cambridge, Massachusetts, USA.
J Immunother Cancer. 2025 Apr 23;13(4):e008987. doi: 10.1136/jitc-2024-008987.
Major histocompatibility complex class I-related protein A and B (MICA/B) are ligands for the natural killer group 2 member D (NKG2D) receptor and are broadly expressed on tumor cells but minimally on normal tissues. When cytotoxic NKG2D-expressing immune cells engage MICA/B, the ligand-expressing cells are targeted for lysis. Cancer cells can evade NKG2D-mediated destruction by shedding MICA/B from their cell surface via proteases present in the tumor microenvironment. CLN-619 is a humanized IgG1 monoclonal antibody (mAb) which binds MICA/B and inhibits shedding resulting in accumulation of MICA/B on the tumor cell surface. CLN-619 may thereby have therapeutic effects in a broad range of malignancies by re-establishing the MICA/B-NKG2D axis to enable NKG2D-mediated, as well as Fc-gamma receptor-mediated, tumor cell lysis.
CLN-619 was characterized for binding epitope and affinity, effects on surface and soluble levels of MICA/B, and in vitro tumor cell killing. In mouse models, the mAb was tested for tumor growth inhibition. The contribution of the Fc-gamma (Fcγ) 1 domain to CLN-619 activity was also assessed.
CLN-619 bound with high affinity to the alpha-3 domain of MICA/B without encumbering the interaction with NKG2D on natural killer cells. CLN-619 increased the level of cell surface expression of MICA/B and concomitantly decreased the levels of soluble MICA/B in cell culture assays. Treatment of cancer cell lines with CLN-619 induced antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. CLN-619 resulted in potent inhibition of tumor growth in multiple xenograft models and increased survival of mice in a disseminated cancer model.
CLN-619 inhibited the shedding of MICA/B to effectively restore cytotoxic signaling pathways in immune cells. Potent antitumor activity of CLN-619 as a monotherapy was observed in several preclinical models. Activity of CLN-619 required a functional Fcγ1 domain, suggesting the requirement of simultaneous engagement of NKG2D and cluster of differentiation 16A (CD16A) on immune cells for optimal cytotoxicity. The preclinical data reported here support the assessment of CLN-619 in patients with cancer.
主要组织相容性复合体I类相关蛋白A和B（MICA/B）是自然杀伤细胞2型成员D（NKG2D）受体的配体，在肿瘤细胞上广泛表达，但在正常组织上表达极少。当表达细胞毒性NKG2D的免疫细胞与MICA/B结合时，表达该配体的细胞会被靶向裂解。癌细胞可通过肿瘤微环境中存在的蛋白酶从其细胞表面脱落MICA/B，从而逃避NKG2D介导的破坏。CLN-619是一种人源化IgG1单克隆抗体（mAb），它能结合MICA/B并抑制其脱落，导致MICA/B在肿瘤细胞表面积累。CLN-619可能通过重建MICA/B-NKG2D轴，使NKG2D介导以及Fc-γ受体介导的肿瘤细胞裂解，从而在多种恶性肿瘤中发挥治疗作用。
对CLN-619的结合表位和亲和力、对MICA/B表面和可溶性水平的影响以及体外肿瘤细胞杀伤作用进行了表征。在小鼠模型中，测试了该单克隆抗体对肿瘤生长的抑制作用。还评估了Fc-γ（Fcγ）1结构域对CLN-619活性的贡献。
CLN-619与MICA/B的α-3结构域高亲和力结合，且不影响其与自然杀伤细胞上NKG2D的相互作用。在细胞培养试验中，CLN-619增加了MICA/B的细胞表面表达水平，同时降低了可溶性MICA/B的水平。用CLN-619处理癌细胞系可诱导抗体依赖性细胞毒性和抗体依赖性细胞吞噬作用。CLN-619在多个异种移植模型中导致肿瘤生长受到有效抑制，并在播散性癌症模型中提高了小鼠的存活率。
CLN-619抑制MICA/B的脱落，有效恢复免疫细胞中的细胞毒性信号通路。在多个临床前模型中观察到CLN-619作为单一疗法具有强大的抗肿瘤活性。CLN-619的活性需要功能性的Fcγ1结构域，这表明免疫细胞上的NKG2D和分化簇16A（CD16A）同时参与才能实现最佳细胞毒性。本文报道的临床前数据支持对癌症患者进行CLN-619评估。
