Inhibrx Inc, La Jolla, California, USA
Inhibrx Inc, La Jolla, California, USA.
J Immunother Cancer. 2023 Jan;11(1). doi: 10.1136/jitc-2022-006116.
As a major driver of lymphocyte proliferation and activation interleukin 2 (IL-2) is a crucial mediator for antitumor responses. Despite promising activity in a subset of patients, wider therapeutic utility of IL-2 (aldesleukin) has been hampered by severe dose-limiting toxicities, the expansion of immunosuppressive regulatory T cells and a poor pharmacokinetic (PK) profile. Recent engineering efforts, including non-α IL-2 variants, have lowered the toxicity profile, but have yet to induce meaningful antitumor activity in a wider patient population.
We engineered INBRX-120, a CD8α-targeted Cisleukin™ molecule consisting of an affinity tuned IL-2 (IL2-x) connected to two high affinity CD8α-specific single domain antibodies via an effector-silenced Fc domain. To show that this large affinity differential enables directed IL-2 cis-signaling exclusively on CD8α-expressing tumoricidal effector cell populations, INBRX-120 effects on target cell expansion, activation and antitumor activity were tested in vitro. In vivo antitumor efficacy was evaluated in syngeneic mouse models alone or in combination with programmed cell death protein-1 (PD-1) blockade. Preclinical safety, as well as pharmacodynamic (PD) and PK profiling was carried out in non-human primates.
INBRX-120 effectively expanded and enhanced the cytotoxic capacity of CD8 T cells and natural killer cells towards tumor cells without affecting regulatory T cells in vitro and in vivo. In syngeneic mouse models, INBRX-120 surrogate showed safe, potent, and durable antitumor efficacy alone and in combination with PD-1 blockade. In non-human primates, INBRX-120 expanded and activated CD8α-expressing effector cells, showed a favorable PK profile, and was well tolerated up to a dose of 1 mg/kg.
Through its unique cis-signaling activity on CD8α-expressing effector cells, INBRX-120 overcomes the major limitations of IL-2-based therapy and effectively harnesses IL-2's potent intrinsic antitumor activity. This novel therapeutic strategy promises safer clinical activity that could induce meaningful antitumor efficacy in a wider set of patients with various cancer indications.
白细胞介素 2（IL-2）作为淋巴细胞增殖和激活的主要驱动因素，是抗肿瘤反应的关键介质。尽管在一部分患者中具有有前景的活性，但由于严重的剂量限制毒性、免疫抑制调节性 T 细胞的扩增以及较差的药代动力学（PK）特征，IL-2（aldesleukin）的更广泛治疗用途受到了阻碍。最近的工程努力，包括非-α IL-2 变体，降低了毒性特征，但尚未在更广泛的患者群体中诱导出有意义的抗肿瘤活性。
我们设计了 INBRX-120，这是一种由亲和力优化的 IL-2（IL2-x）组成的靶向 CD8α 的 Cisleukin™分子，通过一个效应沉默的 Fc 结构域与两个高亲和力的 CD8α 特异性单域抗体相连。为了表明这种大的亲和力差异可以使 IL-2 顺式信号仅在表达细胞毒性效应细胞的 CD8α 上定向，我们在体外测试了 INBRX-120 对靶细胞扩增、激活和抗肿瘤活性的影响。在单独或与程序性细胞死亡蛋白-1（PD-1）阻断联合使用的同种型小鼠模型中评估体内抗肿瘤疗效。在非人类灵长类动物中进行了临床前安全性、药效学（PD）和药代动力学（PK）特征研究。
INBRX-120 可有效扩增和增强 CD8 T 细胞和自然杀伤细胞对肿瘤细胞的细胞毒性能力，而不会影响体内和体外的调节性 T 细胞。在同种型小鼠模型中，INBRX-120 替代物单独使用或与 PD-1 阻断联合使用时具有安全、有效和持久的抗肿瘤疗效。在非人类灵长类动物中，INBRX-120 可扩增和激活表达 CD8α 的效应细胞，表现出有利的 PK 特征，并且在高达 1mg/kg 的剂量下具有良好的耐受性。
通过其在表达 CD8α 的效应细胞上的独特顺式信号活性，INBRX-120 克服了基于 IL-2 治疗的主要限制，并有效地利用了 IL-2 的强大内在抗肿瘤活性。这种新型治疗策略有望具有更安全的临床活性，可以在更广泛的各种癌症适应症患者中诱导出有意义的抗肿瘤疗效。
