Abstract
The unmet need for improved multiple myeloma (MM) therapy has stimulated clinical development of monoclonal antibodies (mAbs) targeting either MM cells or cells of the bone marrow (BM) microenvironment. In contrast to small-molecule inhibitors, therapeutic mAbs present the potential to specifically target tumor cells and directly induce an immune response to lyse tumor cells. Unique immune-effector mechanisms are only triggered by therapeutic mAbs but not by small molecule targeting agents. Although therapeutic murine mAbs or chimeric mAbs can cause immunogenicity, the advancement of genetic recombination for humanizing rodent mAbs has allowed large-scale production and designation of mAbs with better affinities, efficient selection, decreasing immunogenicity, and improved effector functions. These advancements of antibody engineering technologies have largely overcome the critical obstacle of antibody immunogenicity and enabled the development and subsequent Food and Drug Administration (FDA) approval of therapeutic Abs for cancer and other diseases.
Highlights
Despite the landmark approval of the anti-CD20 monoclonal antibodies (mAbs) rituximab for the treatment of B-cell malignancies, to date, no mAb-based therapy has been approved for MM treatment
Studies in early 2000 demonstrated only minimal activity of anti-CD20 rituximab and antibodies against plasma cell-specific CD38 antibodies in MM [1,2,3,4]
The elimination of tumor cells using mAbs depends on Ig-mediated mechanisms, including antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), to activate immune effector cells to lyse target tumor cells (Figure 1(b)) These two mechanisms are believed to have the greatest impact, there are conflicting views of which of these two pathways contributes the most to the response
Summary
Despite the landmark approval of the anti-CD20 mAb rituximab for the treatment of B-cell malignancies, to date, no mAb-based therapy has been approved for MM treatment. The development of effective cytotoxic mAb therapies in MM has been hindered by the lack of uniquely and constitutively expressed target molecules on all MM cells. Studies in early 2000 demonstrated only minimal activity of anti-CD20 rituximab and antibodies against plasma cell-specific CD38 antibodies in MM [1,2,3,4]. Derived mAbs (e.g., against CD40, HM1.24, IGF-1R, CD56, CS1, CD138, CD74, IL-6R, CD38, TRAIL-R1, and the activin receptor type IIA (ActRIIA)) have already demonstrated promising preclinical as well as early clinical activity (Table 1). Targeting bone-MM cell interactions via bone biology modulating factors such as DKK1 and RANKL is likely to trigger anti-MM effects and improves bone disease thereby improving both patient survival as well as patient’s quality of life. The preclinical progress in defining novel MM markers will be continued and subsequently will advance the clinical development of therapeutic mAbs, alone or in combination with other anti-MM agents, to improve patient outcome in MM
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