REGN5458 Demonstrates Antitumor Activity in Myeloma Across Various Preclinical Models

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The investigational antibody construct exploits the power of native effector T cells, supporting antitumor activity shortly after administration.
The investigational antibody construct exploits the power of native effector T cells, supporting antitumor activity shortly after administration.
The following article features coverage from the American Society of Hematology (ASH) 2018 meeting. Click here to read more of Cancer Therapy Advisor's conference coverage.

During a poster presentation at the 2018 American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California, investigators from Regeneron used their platform to discuss REGN5458, a fully human bispecific BCMAxCD3 T-cell engaging antibody that is under preclinical investigation for the treatment of multiple myeloma.1 And, before it has even been tested in humans, the company is positioning it as a rival to anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) therapies, emphasizing that it has similar antitumor activity as does the BCMA-directed CAR-T. 

In lab myeloma cell lines, it was also shown to prompt primary human plasma cells to become more cytotoxic. In immunodeficient mice, REGN5458 suppressed tumor growth. And, even in immunocompetent mice — those which were genetically engineered to express human CD3 — REGN5458 inhibited the growth of syngeneic murine tumors expressing human BCMA.

In cynomolgus monkey models, the company evaluated the pharmacology of REGN5458, and demonstrated the experimental agent bound to both CD3 and BCMA, leading to a reduction of BCMA-positive plasma cells in the bone marrow.

But Regeneron is not discounting the value or potential of CAR-T; in fact, the company is working on its own versions, albeit with slightly different elements than some of the other companies that have products in the pipeline.

Scientists used the lentiviral constructs (containing a single-chain variable fragment binding domain) from REGN5458's BCMA binding arm, added 4-1BB and CD3z signaling domains, and transduced T cells to express a novel CAR construct with these elements.

To prove the viability of their investigational construct, researchers from Regeneron compared the activity of REGN5458 (a BCMAxCD3 bsAb) with the BCMA CAR-T in patient cells. According to the investigators, REGN5458 had "similar targeted cytotoxicity of myeloma cell lines and primary patient blasts in vitro, and were capable of clearing established systemic OPM-2-luciferase myeloma tumors in NSG mice." In addition, REGN5458 prompted tumor clearance within 4 days of injection, whereas in the BCMA CAR-T they examined, tumor cells proliferated for 10 to 14 days postinjection before tumor clearance could begin. The presenters attributed the prompt activity of the bispecific BCMAxCD3 T-cell engaging antibody to the fact that the product interacts with native effector T cells. This is unlike CAR-T; in CAR-T, T-cell expansion of the engineered construct is a prerequisite for an antitumor response.

Taken together, these data "provide a strong rationale for clinical testing of REGN5458 in patients with MM," the scientists concluded.

Disclosure: This study was funded by Regeneron.

Read more of Cancer Therapy Advisor's coverage of the ASH 2018 meeting by visiting the conference page.

Reference

  1. Dilillo DJ, Olson K, Mohrs K, et al. REGN5458, a bispecific BCMAxCD3 T cell engaging antibody, demonstrates robust in vitro and in vivo anti-tumor efficacy in multiple myeloma models, comparable to that of BCMA CAR T cells. Poster presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018: San Diego, CA. Poster 1944.
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