Bispecific Antibodies in Multiple Myeloma: Do These T cell-Recruiting Antibodies Make a Difference?

Study of ISB 1342, a CD38/CD3 Bispecific Antibody, in Subjects With Previously Treated Multiple Myeloma

NCT03309111

Ichnos Sciences SA

125 patients

Nine centers around the United States

This is a phase I open-label, two part dose-escalation and cohort expansion study of ISB 1342, a bispecific antibody directed at CD38 and CD3, for patients with progressive or relapsed multiple myeloma (MM) refractory to proteasome inhibitors, immunomodulators, and daratumumab. The primary outcome measures are maximum tolerated dose defined by the number of dose-limiting toxicities, objective response according to the International Myeloma Working Group (IMWG) response criteria, and the frequency and severity of adverse events. Secondary outcomes will measure maximum serum concentration, immunogenecity by antidrug antibody formation, and disease control rate. ISB 1342 will be administered by intravenous infusion on day 1 and day 15 of each 28-day treatment cycle at escalating dose levels.

Despite advances in the treatment of MM, current therapies fail to cure most patients with MM due to intrinsic resistance, acquired resistance, and/or persistent minimal residual disease leading to subsequent relapse. Thus, new therapies with a more potent mechanism of action are needed.¹  Bispecific antibody therapy has proven to be clinically relevant in other hematologic malignancies through an alternative mechanism of action.²  In acute lymphoblastic leukemia, for instance, blinatumumab has moved into common usage before stem cell transplantation for patients with either refractory disease or with evidence of measurable residual disease. Bispecific antibodies induce redirected T-cell lysis of tumor cells by simultaneous engagement of endogeneous T cells, via binding to CD3, and the tumor cell, via any extracellular tumor-associated antigen.³  CD38 is a tumor-associated antigen with near-universal expression in MM⁴  and has been validated as a target in MM with the human monoclonal antibody daratumumab. While daratumumab monotherapy is associated with an approximately 35 percent overall response rate (ORR) and an 80 to 90 percent ORR when combined with other treatment modalities,¹  not all patients respond, and many eventually develop progressive disease. The efficacy of daratumumab is limited by the inability to stimulate cytotoxic T-cell killing of myeloma cells. In preclinical studies, ISB 1342 was able to overcome this limitation by redirecting the cytotoxic potential of T cells to human myeloma cell lines in vitro and in mouse xenograft models.⁵  The aim of this study is to evaluate the safety, tolerability, and efficacy of monotherapy with ISB 1342 in relapsed/refractory patients.

The development of numerous treatment strategies aimed at overcoming the progressive immune dysfunction in myelomagenesis has been promising. Bispecific antibodies in particular represent a powerful tool for inciting major histocompatibility complex–independent T-cell response against cancer. The first bispecific antibody construct with available clinical data in MM is the B-cell maturation antigen–targeting molecule AMG 420 showing a favorable adverse event profile and a 70 percent RR (7 of 10) at the recommended study dose of 400 µg/d.⁶  Data presented at the 2019 ASH Annual Meeting showed promising results for another B-cell maturation antigen bispecific antibody, CC-93269, with an ORR of 89 percent and a 44 percent complete response rate at the highest dose of 10 mg.⁷  Like AMG 420 and CC-93269, ISB 1342 is being tested in a relapsed/refractory setting. However, the efficacy of other bispecific antibodies have been shown to be higher in patients with less tumor burden, suggesting that earlier timing is necessary for optimal effect.⁸  Since CD38 is highly expressed in the early stages of plasma cell clonal evolution, it will be interesting to evaluate whether an anti-CD38 bispecific antibody could prevent or delay progression to symptomatic MM. However, the broad expression of CD38 on other cells, such as lymphocytes, natural killer cells, dendritic cells, and bone marrow progenitor cells,⁹  raises the question of off-target toxicity. Next to timing and toxicity profile, resistance mechanisms due to shedding/downregulation of CD38 need to be studied further. This also raises the question of the necessity of CD38 expression upon start of treatment. Additionally, studying biomarkers for therapy efficacy and best drug combinations will be necessary to see if an anti–CD3/CD38 bispecific antibody could be clinically succesful. A second trial of a bispecific antibody dual targeting CD3 and CD38 (AMG 424) is currently recruiting (NCT03445663). Additional studies are investigating other known MM-associated antigens such as SLAMF7 and GPRC5D (NCT03399799) bispecific antibodies. While many questions remain to be answered, awaiting current trials, bispecific antibodies seem to provide an off-the-shelf alternative in the arsenal of antimyeloma immunotherapy.