Targeting Multiple Myeloma with AMG 424, a Novel Anti-CD38/CD3 Bispecific T-cell-recruiting Antibody Optimized for Cytotoxicity and Cytokine Release
Targeting Multiple Myeloma with AMG 424, a Novel Anti-CD38/CD3 Bispecific T-cell-recruiting Antibody Optimized for Cytotoxicity and Cytokine Release
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DOI：
10.1158/1078-0432.ccr-18-2752
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发表时间：
2019-07-01
影响因子：
11.5
通讯作者：
Nolan-Stevaux, Olivier
中科院分区：
文献类型：
--
作者：
de Zafra, Christina L. Zuch;Fajardo, Flordeliza;Nolan-Stevaux, Olivier
目的：尽管多发性骨髓瘤的治疗取得了进展，但仍需要新的治疗方法来引起更深刻的临床反应。由双特异性抗体向癌细胞募集T细胞而触发的T细胞重定向裂解是一种临床验证的抗血液系统恶性肿瘤的作用机制，而CD38是一种肿瘤相关抗原，在多发性骨髓瘤中几乎普遍表达。因此，抗CD38/CD3双特异性T细胞募集抗体有可能成为治疗多发性骨髓瘤的有效新方法。实验设计：体外和体内研究了不同CD38和CD3亲和力的抗CD38/CD3 XmAbT细胞募集抗体对癌细胞的重定向T细胞杀伤活性、较低水平的细胞因子释放以及在存在高水平可溶性CD38的情况下的效力。在食蟹猴身上进一步测试B细胞耗竭和细胞因子释放特性。结果：AMG 424在体外能够杀死高水平和低水平表达CD38的癌细胞，并触发T细胞增殖，但细胞因子释放减弱。在体内，AMG 424在骨髓侵袭性小鼠癌症模型中诱导肿瘤生长抑制，并在食蟹猴体内诱导外周B细胞耗尽，而不会引发过度的细胞因子释放。结论：这些发现支持AMG 424的临床开发，AMG 424是一种亲和力优化的T细胞募集抗体，有可能在多发性骨髓瘤患者中引发显著的临床活性。
Purpose: Despite advances in the treatment of multiple myeloma, new therapies are needed to induce more profound clinical responses. T-cell-redirected lysis triggered by bispecific antibodies recruiting T cells to cancer cells is a clinically validated mechanism of action against hematologic malignancies and CD38 is a tumor-associated antigen with near-universal expression in multiple myeloma. Thus, an anti-CD38/CD3 bispecific T-cell-recruiting antibody has the potential to be an effective new therapeutic for multiple myeloma.Experimental Design: Anti-CD38/CD3 XmAb T-cellrecruiting antibodies with different affinities for CD38 and CD3 were assessed in vitro and in vivo for their redirected T-cell lysis activity against cancer cell lines, their lower levels of cytokine release, and their potency in the presence of high levels of soluble CD38. Select candidates were further tested in cynomolgus monkeys for B-cell depletion and cytokine release properties.Results: AMG 424 was selected on the basis of its ability to kill cancer cells expressing high and low levels of CD38 in vitro and trigger T-cell proliferation, but with attenuated cytokine release. In vivo, AMG 424 induces tumor growth inhibition in bone marrow-invasive mouse cancer models and the depletion of peripheral B cells in cynomolgus monkeys, without triggering excessive cytokine release. The activity of AMG 424 against normal immune cells expressing CD38 is also presented.Conclusions: These findings support the clinical development of AMG 424, an affinity-optimized T-cell-recruiting antibody with the potential to elicit significant clinical activity in patients with multiple myeloma.