Abstract
Here we review the insights and lessons learned from early clinical trials of T-cell engaging bispecific antibodies (BsABs) as a new class of biotherapeutic drug candidates with clinical impact potential for the treatment of multiple myeloma (MM). BsABs are capable of redirecting host T-cell cytotoxicity in an MHC-independent manner to malignant MM clones as well as immunosuppressive myeloid-derived suppressor cells (MDSC). T-cell engaging BsAB targeting the BCMA antigen may help delay disease progression in MM by destroying the MM cells. T-cell engaging BsAB targeting the CD38 antigen may help delay disease progression in MM by depleting both the malignant MM clones and the MDSC in the bone marrow microenvironment (BMME). BsABs may facilitate the development of a new therapeutic paradigm for achieving improved survival in MM by altering the immunosuppressive BMME. T-cell engaging BsiABs targeting the CD123 antigen may help delay disease progression in MM by depleting the MDSC in the BMME and destroying the MM stem cells that also carry the CD123 antigen on their surface.
Highlights
Specialty section: This article was submitted to Hematologic Malignancies, a section of the journal Frontiers in Oncology
We review the insights and lessons learned from early clinical trials of T-cell engaging bispecific antibodies (BsABs) as a new class of biotherapeutic drug candidates with clinical impact potential for the treatment of multiple myeloma (MM)
Expanded populations of myeloid-derived suppressor cells (MDSC), representing CD33+CD123+ immature myeloid cells within the bone marrow mononuclear cell fraction contribute to the immunosuppressive bone marrow microenvironment (BMME) by inhibiting both memory and cytotoxic effector T-cell populations as well as natural killer (NK) cells, thereby promoting the immune evasion of MM clones [4, 9,10,11,12,13,14,15, 20] (Figure 1)
Summary
MM is a heterogenous hematologic malignancy and relapses due to resistant disease are common [1,2,3,4]. Resistance of the malignant clones to multiple drugs hampers a more successful treatment outcome after contemporary standard of care regimens in MM [1,2,3,4]. Personalized therapy platforms have been designed to overcome the drug resistance, including precision medicines, kinase inhibitors, CAR-T cells, and antibody therapeutics [5,6,7,8]. Effective treatment of patients with drug-resistant relapsed disease continues to be an unmet medical need [1,2,3,4]
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