Despite several approved therapies, multiple myeloma (MM) remains an incurable disease with high unmet medical need. “Off-the-shelf” T-cell bispecific antibodies (TCBs) targeting B-cell maturation antigen (BCMA) and GPRC5D have demonstrated high objective response rates in heavily pretreated patients with MM; however, primary resistance, short duration of response, and relapse driven by antigen shift frequently occur. Although GPRC5D represents the most selective target in MM, recent findings indicate antigen loss occurs more frequently than with BCMA. Thus, anti-GPRC5D immunotherapies must hit hard during a short period of time to kill as many myeloma cells as possible. Here, we characterize forimtamig, a novel GPRC5D-targeting TCB with 2+1 format, using preclinical models of MM. Bivalent binding of forimtamig to the N terminus of GPRC5D confers higher affinity than classical 1+1 TCB formats correlating with formation of more stable immunological synapses and higher potency in tumor cell killing and T-cell activation. Using an orthotopic mouse model of MM, forimtamig recruited T effector cells to the bone marrow and induced rapid tumor killing even after the introduction of step-up dosing to mitigate cytokine release. Combination of forimtamig with standard-of-care agents including anti-CD38 antibodies, immunomodulatory drugs, and proteasome inhibitors improved depth and duration of response. The combination of forimtamig with novel therapeutic agents including BCMA TCB and cereblon E3 ligase modulatory drugs was potent and prevented occurrence of GPRC5D-negative tumor relapse. Forimtamig is currently being evaluated in phase 1 clinical trials in patients with relapsed and refractory MM for monotherapy and in combination treatments. This trial was registered at www.ClinicalTrials.gov as #NCT04557150.

中文翻译：

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Forimtamig，一种新型靶向 GPRC5D 的 T 细胞双特异性抗体，具有 2+1 形式，用于治疗多发性骨髓瘤


尽管有几种批准的疗法，但多发性骨髓瘤 （MM） 仍然是一种无法治愈的疾病，医疗需求未得到满足。靶向 B 细胞成熟抗原 （BCMA） 和 GPRC5D 的“现成”T 细胞双特异性抗体 （TCB） 在既往接受过大量治疗的 MM 患者中显示出高客观缓解率;然而，原发性耐药、反应持续时间短和抗原转移驱动的复发经常发生。尽管 GPRC5D 是 MM 中最具选择性的靶标，但最近的研究结果表明抗原丢失比 BCMA 更频繁。因此，抗 GPRC5D 免疫疗法必须在短时间内重创，以杀死尽可能多的骨髓瘤细胞。在这里，我们使用 MM 的临床前模型表征了福林他米格，一种具有 2+1 格式的新型 GPRC5D 靶向 TCB。福林他米与 GPRC5D 的 N 末端的二价结合赋予比经典的 1+1 TCB 格式更高的亲和力，与更稳定的免疫突触的形成以及更高的肿瘤细胞杀伤和 T 细胞活化效力相关。使用 MM 的原位小鼠模型，forimtamig 将 T 效应细胞募集到骨髓中，即使在引入递增剂量以减轻细胞因子释放后，也能诱导快速肿瘤杀伤。forimtamig 与标准护理药物（包括抗 CD38 抗体、免疫调节药物和蛋白酶体抑制剂）联合使用改善了反应的深度和持续时间。forimtamig 与 BCMA TCB 和 cereblon E3 连接酶调节药物等新型治疗药物的组合有效，可预防 GPRC5D 阴性肿瘤复发的发生。Forimtamig 目前正在复发和难治性 MM 患者的 1 期临床试验中接受单药治疗和联合治疗。此试用版已在 www.ClinicalTrials.gov as #NCT04557150。