A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo

Abstract

B-cell maturation antigen (BCMA) is a highly plasma cell-selective protein that is expressed on malignant plasma cells of multiple myeloma (MM) patients and therefore is an ideal target for T-cell redirecting therapies. We developed a bispecific T-cell engager (BiTE) targeting BCMA and CD3ε (BI 836909) and studied its therapeutic impacts on MM. BI 836909 induced selective lysis of BCMApositive MM cells, activation of T cells, release of cytokines and T-cell proliferation; whereas BCMA-negative cells were not affected. Activity of BI 836909 was not influenced by the presence of bone marrow stromal cells, soluble BCMA or a proliferation-inducing ligand (APRIL). In ex vivo assays, BI 836909 induced potent autologous MM cell lysis in both, newly diagnosed and relapsed/ refractory patient samples. In mouse xenograft studies, BI 836909 induced tumor cell depletion in a subcutaneous NCI-H929 xenograft model and prolonged survival in an orthotopic L-363 xenograft model. In a cynomolgus monkey study, administration of BI 836909 led to depletion of BCMA-positive plasma cells in the bone marrow. Taken together, these results show that BI 836909 is a highly potent and efficacious approach to selectively deplete BCMA-positive MM cells and represents a novel immunotherapeutic for the treatment of MM.

Molecular imaging reveals biodistribution of P-cadherin LP-DART bispecific and trafficking of adoptively transferred T cells in mouse xenograft model

“…Although spleen showed significantly higher accumulation of P-cadherin LP-DART compared to control LP-DART at 48 h and 96 h, the quantities were very low. short plasma half-life requires continuous infusion and frequent administration of the drug, compared to weekly or bi-weekly administration of Fc-containing bispecific molecules [23,24]. We also compared the exposure of P-cadherin LP-DART when administered intravenously or subcutaneously using FMT imaging.…”

Immunotherapy for Multiple Myeloma

“…A CD19/CD3 bispecific antibody designed in the BiTE format, blinatumomab, was reported to be effective in patients with B-cell malignances, such as relapsed or refractory B-cell precursor acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma [45][46][47]. The BCMA/CD3 bispecific T-cell engager induced myeloma lysis in vitro and in vivo [48,49]. Topp et al showed that treatment with AMG 420, a BCMA bispecific T-cell engager in the BiTE antibody construct, induced MRD-negative CR in a phase I study of 42 RRMM patients who had received a median of 4 (range 2-13) prior treatment lines [21].…”

Hematopoietic stem cell transplantation for blood cancers in the era of precision medicine and immunotherapy

“…Trudel et al recently reported their experience with what to our knowledge is the most well studied of these immunoconjugates, GSK2857916, and found that anemia, thrombocytopenia, and low‐grade corneal events were common (57%); however, the ORR was 60% in heavily pretreated patients . Bispecific antibodies targeting BCMA in combination with CD3 also are being actively investigated, with preliminary results demonstrating rates of response and toxicity profiles similar to those noted with other BCMA‐targeted immunotherapies . Other immunotherapeutic targets currently under active study include CD38, CD138, CD19, kappa light chain, NY‐ESO‐1, and SLAMF7.…”