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Bispecific BCMA-CD3 Antibodies Block Multiple Myeloma Tumor Growth.

ABSTRACT: BCMA antigen is overexpressed in multiple myeloma cells and has been shown to be a promising target for novel cellular and antibody therapeutics. The humanized BCMA (clone 4C8A) antibody that effectively targeted multiple myeloma in a CAR (chimeric antigen receptor) format was used for designing several formats of bispecific BCMA-CD3 antibodies. Several different designs of univalent and bivalent humanized BCMA-CD3 CrossMAB and BCMA-FAB-CD3 ScFv-Fc antibodies were tested for binding with BCMA-positive cells and T cells and for killing by real time cytotoxic activity and IFN-gamma secretion with CHO-BCMA target cells and with multiple myeloma MM1S and H929 cell lines. All BCMA-CD3 antibodies demonstrated specific binding by FACS to CHO-BCMA, multiple myeloma cells, and to T cells with affinity Kd in the nM range. All antibodies with T cells specifically killed CHO-BCMA and multiple myeloma cells in a dose-dependent manner. The BCMA-CD3 antibodies with T cells secreted IFN-gamma with EC₅₀ in the nM range. In addition, three BCMA bispecific antibodies had high in vivo efficacy using an MM1S xenograft NSG mouse model. The data demonstrate the high efficacy of novel hBCMA-CD3 antibodies with multiple myeloma cells and provide a basis for future pre-clinical and clinical development.

SUBMITTER: Wu L

PROVIDER: S-EPMC9139578 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Bispecific BCMA-CD3 Antibodies Block Multiple Myeloma Tumor Growth.

Wu Lijun L Huang Yanwei Y Sienkiewicz John J Sun Jinying J Guiang Liselle L Li Feng F Yang Liming L Golubovskaya Vita V

Cancers 20220520 10

BCMA antigen is overexpressed in multiple myeloma cells and has been shown to be a promising target for novel cellular and antibody therapeutics. The humanized BCMA (clone 4C8A) antibody that effectively targeted multiple myeloma in a CAR (chimeric antigen receptor) format was used for designing several formats of bispecific BCMA-CD3 antibodies. Several different designs of univalent and bivalent humanized BCMA-CD3 CrossMAB and BCMA-FAB-CD3 ScFv-Fc antibodies were tested for binding with BCMA-po ...[more]

PMID: 35626122

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Project description:BackgroundHighly efficient targeted therapy is urgently needed for multiple myeloma (MM). Mesenchymal stem cells (MSCs) are an attractive candidate of cell-based, targeted therapy due to their inherent tumor tropism. However, there is still no MSCs-based tandem diabody for treating MM.MethodsHere, we designed a dual-target therapeutic system in which human umbilical cord MSCs (UCMSCs) were engineered to produce and deliver Tandab (CD3/BCMA), a tetravalent bispecific tandem diabody with two binding sites for CD3 and two for B-cell maturation antigen (BCMA). Western blot and flow cytometry were used to confirm the lentivirus-mediated construction of UCMSCs for diabody expression. The tropism of MSCs towards H929 cells in vitro was determined by migration assays, and the in vivo homing capacity of MSCs was analyzed by immunofluorescence staining. The activation and antitumor efficacy of human T cells mediated by MSCs secreting Tandab (CD3/BCMA) were evaluated in vitro. Finally, an MM xenograft NOD/SCID mouse model was established to investigate the therapeutic effect in vivo.ResultsWe successfully constructed MSCs that can continuously secrete bioactive Tandab (CD3/BCMA), whereby lentiviral transduction did not affect the morphology, proliferation, and lineage differentiation potential of the MSCs. The tropism of MSC-Tandab for MM was verified both in vitro and in vivo. Furthermore, MSC-Tandab promoted the expansion and activation of primary human T cells and induced healthy donor T cells to selectively eliminate BCMA-positive cell lines and primary blasts from patients but not BCMA-negative cells. A similar ability was also observed in the patient-derived T cells. Finally, MSC-Tandab significantly alleviated the MM xenograft tumor burden in NOD/SCID mice without toxic side effects in vivo, whereby the cytokine levels (IFN-γ) in the peripheral blood (PB) were higher in the MSC-Tandab group, and the tumor infiltration of T cells was significantly enhanced.ConclusionsThese results suggest that UCMSCs releasing Tandab (CD3/BCMA) are a promising new tool for the treatment of MM, opening a new avenue for the development of cell-based therapy.

Dataset Information

Bispecific BCMA-CD3 Antibodies Block Multiple Myeloma Tumor Growth.

Publications

Bispecific BCMA-CD3 Antibodies Block Multiple Myeloma Tumor Growth.

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