Anti-BCMA BiTE AMG 701 Shows Preclinical Promise in Multiple Myeloma

AMG 701, a half-life—extended anti-BCMA bispecific T-cell engager (BiTE) showed promising in vitro antimyeloma activity and characteristics suitable for once-weekly dosing in patients with multiple myeloma, according to findings presented at the 17th International Myeloma Workshop.

At the meeting, lead investigator Shih-Feng Cho, MD, PhD, Dana Farber Cancer Institute and Kaohsiung Medical University described the potential of this agent to induce T-cell directed lysis of multiple myeloma cells, and to overcome the immunosuppressive bone marrow microenvironment when combined with T cells pretreated in vitro with immunomodulatory drugs (IMiDs).¹

BCMA is an important target in the treatment of multiple myeloma because it is highly and specifically expressed on normal plasma cells and multiple myeloma cells. AMG 701 contains an Fc domain which yields a longer serum half-life for the molecule. The agent is currently being investigated as a monotherapy in an ongoing clinical trial (NCT03287908).²

Cho described the preclinical investigation of AMG 701, including the potency of multiple myeloma cell lysis, immunomodulatory effects, and potential therapeutic partners.

AMG 701 significantly induced T-cell mediated lysis of multiple myeloma cell lines in vitro in a dose-dependent manner, including IMiD-resistant cell lines. The agent also induced dose-dependent killing of cells from patients with relapsed/refractory multiple myeloma when added to bone marrow mononuclear cells in vitro.

AMG 701 induced proliferation of central memory (CM) and effector memory (EM) T cells, as well as enhancing the proliferation and differentiation of both CD4+ and CD8+ T cells from naïve to CM and EM in vitro.

When T cells were pretreated with the IMiDs lenalidomide (Revlimid) or pomalidomide (Pomalyst) followed by coculture with multiple myeloma cells, AMG 701 enhanced the lysis of the multiple myeloma cells. Furthermore, AMG 701 in combination with IMiD-exposed T cells was able to overcome the protection of multiple myeloma cells by the bone marrow microenvironment (osteoclasts or bone marrow stromal cells) in vitro, again enhancing multiple myeloma cell lysis and at earlier time points.

AMG 701 added to IMiD pretreated T cells increased effector T cell function in vitro as measured by increased CD107a degranulation, and interferon gamma and tumor necrosis alpha production, and proliferation in a higher percentage of CD8+ than CD4+ T cells.

IMiD pretreatment also improved AMG 701—induced T cell modulation in vitro in a time-dependent fashion, with an increased in CD4+ and CD8+ CM and EM cells over 7 days of coculture.

In the NCI-H920 mouse xenograft model of established multiple myeloma disease, AMG 701 blocked tumor growth 5 days after the first injection and completely eradicated tumor growth after 3 injections at all dose levels (0.02, 0.2, 2 mg/kg), without drug-related adverse effects in the host.

Then mice were treated from day 15 until study end with daily lenalidomide, AMG 701 once weekly or a combination of weekly doses of AMG 701 and daily doses of lenalidomide. Significant antitumor activity was observed at 2 days after treatment with the combination treatment and tumor volume remained low over 45+ days of study. In contrast, mice treated with AMG 701 alone or lenalidomide alone experienced an increase in tumor volume (regrowth of tumor) by study end after an initial decrease.

AMG 701 induced T-cell proliferation, activation, and memory T cell differentiation in vitro, particularly in CD38+ T cells rather than CD4+ T cells. AMG 701 induced significant T cell-mediated multiple myeloma cell lysis in vitro which occurred at a low effector/target ratio and at low concentrations. Combining AMG 701 with IMiD-pretreated T cells further enhanced multiple myeloma cell killing in vitro. AMG 701 was able to augment multiple myeloma cell killing even in the presence of protective cells from the bone marrow environment, as well as enhance effector T cell function and immunomodulation.

Cho concluded that these results support the current phase I clinical trial of AMG 701 monotherapy in patients with relapsed/refractory multiple myeloma, but also provide a rationale for clinical investigation of AMG 701 plus an IMiD, given the enhanced antimyeloma activity of this combination.

References

1. Cho S-F, Lin L, Xing L, et al. AMG 701, a half-life extended anti-BCMA BiTE^®, potently induces T cell-redirected lysis of human multiple myeloma cells and can be combined with IMiDs to overcome the immunosuppressive bone marrow microenvironment. Presented at: The 17th International Myeloma Workshop; Sept. 12-15, 2019; Boston, MA. AB169.
2. NCT03287908: A phase 1 study of AMG 701 in subjects with multiple myeloma. NIH US National Library of Medicine. Posted September 19, 2017. Accessed September 16, 2019. https://clinicaltrials.gov/ct2/show/NCT03287908.

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