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by Dr. C.H. Weaver M.D. 5/2022

Bispecific antibody constructs represent an innovative immunotherapy approach that helps the body’s immune system target cancer cells and appears very promising for the treatment of multiple myeloma. Bispecific antibodies or BiTE which is short for "bispecific T cell engager" are antibodies with two arms. One arm of the drug attaches to a specific protein on the cancer cell. The other arm of the BiTE activates immune cells in the patient to kill the cancer cells.1

REGN5458 is a BCMA x CD3 bispecific antibody designed to bind to BCMA on multiple myeloma cells and the CD3 receptor on T-cells, bridging them together and activating T-cell killing of the cancerous myeloma cells. REGN5458 was invented using Regeneron's next generation VelocImmune® "human antibody mouse" technology, together with its VelociBi™ platform. These allow for the creation of bispecific antibodies that closely resemble natural human antibodies with no linkers or artificial sequences.1

Multiple Myeloma CancerConnect 490

Initial results evaluating REGN5458 were presented at the American Society of Hematology (ASH) Annual Meeting in December 2019 and updated in 2021. Several dose levels of REGN5458 were evaluated in refractory myeloma patients previously treated with a median of seven lines of prior systemic therapy, all of whom had failed CD38 antibody treatment. Responses were observed in 57% of patients, including 75% treated at the highest administered REGN5458 dose.

Results were updated at the 2021 ASH annual meeting. The new results from the Phase 1 portion of the Phase 1/2 trial in patients with relapsed/refractory multiple myeloma found a 51% overall response rate across all dose groups, rising to 75% in patients who received higher doses of REGN5458 (200-800 mg).2

  • 8 months from the time of response, there was a 90% probability of being event-free (95% CI: 73%, 97%), defined by the absence of disease progression or death. The estimated median duration of response had not yet been reached at the time of data cutoff.
  • Responses occurred rapidly, usually within the first month of treatment, and continue to deepen with longer treatment; the higher dose groups currently have substantially shorter follow up.
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Multiple Myeloma Newsletter 490

Cytokine release syndrome (CRS) was reported in 38% of patients (n=28), the majority of which were mild. The other most common side effects were fatigue, fever, nausea, and anemia. There were 5 deaths in the trial, all due to infection; none were considered related to the study medication by investigators. REGN5458 is currently under clinical development and its safety and efficacy have not been fully evaluated by any regulatory authority.

Cevostamab - in Development

Cevostamab is a T-cell engaging bispecific antibody designed to target FcRH5 on myeloma cells and CD3 on T cells. FcRH5 is a unique and differentiated target, expressed on nearly all myeloma cells. Cevostamab has a structure similar to that of a natural human antibody in that it has two ‘Fab’ regions, but is different from naturally-occurring antibodies in that one ‘Fab’ region targets FcRH5 and the other ‘Fab’ region targets CD3. This dual targeting activates and re-directs a patient’s existing T cells to engage and eliminate target FcRH5-expressing myeloma cells by releasing cytotoxic proteins into the myeloma cells.

References:

  1. Leukemia; 2019; DOI:10.1038/s41375-019-0435-7
  2. https://www.prnewswire.com/news-releases/new-regn5458-bcmaxcd3-phase-1-data-show-75-response-rate-at-highest-dose-levels-studied-in-patients-with-heavily-pretreated-multiple-myeloma-301442629.html