Targeting Multiple Myeloma with AMG 424, a Novel Anti-CD38/CD3 Bispecific T-cell–recruiting Antibody Optimized for Cytotoxicity and Cytokine Release

Abstract

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.

Perspective: Designing T-Cell Engagers With Better Therapeutic Windows

“…Importantly, in the context of human IgG heterodimeric bispecific antibodies, F2 family members retained full efficacy against cancer target cells while demonstrating low levels of cytokine release (30). Consistent with our results, recent studies by Zuch de Zafra et al (31) and Li et al (32) also demonstrated that T-cell mediated cytotoxicity can be decoupled from cytokine release when using TCEs. Li et al further showed that initial release of TNF from T-cells was the primary culprit driving CRS by triggering downstream proinflammatory cytokine release from monocytes.…”

Immunotherapy in Multiple Myeloma

“…AMG424, a BiTE targeting CD38, has also been reported to show potent activity against MM cell lines, with both low and high CD38 expression in vitro [121]. This agent also inhibited tumor growth in murine models and showed acceptable toxicity in monkeys.…”

“…This agent also inhibited tumor growth in murine models and showed acceptable toxicity in monkeys. The expression of CD38 on NK cells, monocytes and a subset of B cells raises the question of the impact of this therapy on other immune effector cells [121,122]. Zuch de Zafra et al showed that although therapeutic doses of AMG424 resulted in B cell depletion, significantly higher doses were required to affect NK cell, monocytes and T-cells [121].…”

The Many Facets of CD38 in Lymphoma: From Tumor–Microenvironment Cell Interactions to Acquired Resistance to Immunotherapy

“…Anti-CD38/CD3 bispecific antibodies have not yet been clinically developed but have the potential to become curative options for multiple myeloma and other lymphoid malignancies, given the widespread expression of CD38 on malignant cells. Zuch de Zafra and coworkers have recently demonstrated considerable in vitro and in vivo activity of the novel anti-CD38/CD3 bispecific antibody AMG 424 against high and low CD38-expressing cells, such as those previously exposed to Daratumumab [107]. Clinical trials assessing the activity of such therapy in r/r MM are currently recruiting patients (NCT03309111, clinicaltrials.gov), and optimal results may extend their use to other lymphoid malignancies.…”