Abstract
Today, monoclonal antibodies (mAbs) are a widespread and necessary tool for biomedical science. In the hematological cancer field, since rituximab became the first mAb approved by the Food and Drug Administration for the treatment of B-cell malignancies, a number of effective mAbs targeting lineage-specific antigens (LSAs) have been successfully developed. Non-LSAs (NLSAs) are molecules that are not restricted to specific leukocyte subsets or tissues but play relevant pathogenic roles in blood cancers including the development, proliferation, survival, and refractoriness to therapy of tumor cells. In consequence, efforts to target NLSAs have resulted in a plethora of mAbs—marketed or in development—to achieve different goals like neutralizing oncogenic pathways, blocking tumor-related chemotactic pathways, mobilizing malignant cells from tumor microenvironment to peripheral blood, modulating immune-checkpoints, or delivering cytotoxic drugs into tumor cells. Here, we extensively review several novel mAbs directed against NLSAs undergoing clinical evaluation for treating hematological malignancies. The review focuses on the structure of these antibodies, proposed mechanisms of action, efficacy and safety profile in clinical studies, and their potential applications in the treatment of hematological malignancies.
Highlights
Cancer treatment is expanding from non-specific cytotoxic chemotherapies to targeted therapies as a consequence of increased knowledge of the pathogenesis of cancer that leads to a better design of treatments to inhibit tumor growth and spread
Results from a phase II study (NCT00094848) demonstrated that mapatumumab was capable of producing clinical responses when used as single agent in patients with B-cell non-Hodgkin lymphoma (B-NHL) [181], follicular lymphoma (FL)
Most of the antibodies already approved target lineage-specific antigens (LSAs), whereas the majority of agents in development for hematological malignancies targets NLSAs. This situation reflects a paradigm shift in the criteria followed to select a target to develop as novel immune therapy in blood malignancies care. The impact of this change is still unknown in disorders where monoclonal antibodies (mAbs) targeting LSAs were not used, or resulted to be ineffective, such as MM, acute myeloid leukemia (AML), or T-NHL
Summary
Cancer treatment is expanding from non-specific cytotoxic chemotherapies to targeted therapies as a consequence of increased knowledge of the pathogenesis of cancer that leads to a better design of treatments to inhibit tumor growth and spread. MAb, monoclonal antibody; MOA, mechanisms of action; HMs, hematological malignancies; Ch, human–mouse chimeric; Fh, fully human; Hz, humanized; m, mouse; Glyco-Fc, glycoengineered Fc fragment; CDC, complementdependent cytotoxicity; ADCC, antibody-dependent cell-mediated cytotoxicity; ADCP, antibody-dependent cell-mediated phagocytosis; PCD, programmed cell death; B-NHL, B-cell non-Hodgkin’s lymphoma; HL, Hodgkin’s lymphoma; CLL, chronic lymphocytic leukemia; FL, follicular lymphoma; DLBCL, diffuse large B-cell lymphoma; MCL, mantle cell lymphoma; MM, multiple myeloma; B-ALL, B-cell acute lymphoblastic leukemia; T-PLL, T-cell prolymphocytic leukemia; PTCL, peripheral T-cell lymphoma; CTCL, cutaneous T-cell lymphoma; ATL, adult T-cell leukemia and lymphoma; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; CMML, chronic myelomonocytic leukemia; MDS, myelodysplastic syndrome; DC, dendritic cells; disc., discontinued in hematological malignancies; NCT, number of clinical trial (clinicaltrials.gov); C, completed; R, recruiting; T, terminated; ANR, active non-recruiting; NYR, not yet recruiting; E, enrolling by invitation; T, terminated; S, suspended; W, withdrawn.
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