Monoclonal Antibody-Directed Therapies for the Management of Multiple Myeloma

Noa Biran, MD
Published: Monday, May 11, 2015
John Theurer Cancer CenterNoa Biran, MD
Noa Biran, MD
Myeloma Division
John Theurer Cancer Center
Hackensack University Medical Center
Hackensack, NJDr. Catherine M. Diefenbach
The overall survival (OS) of patients with multiple myeloma (MM) has improved significantly over the past decade with the development of novel therapies.1 However, as patients relapse, their disease becomes resistant to existing therapy. Several monoclonal antibodies (mAbs) with MM cell antigen or bone marrow targets have exhibited strong antimyeloma activity and may become potential therapeutic agents.

Structure and Mechanism of Action of Monoclonal Antibodies

Antibodies are made of two or more pairs of heavy and light chains joined by disulphide bonds, comprising a variable and a constant region (Figure). The variable regions differ in structure from one antibody to another and contain the combining site. The constant region is unchanging within a given class and is responsible for effector functions.2 It has been proposed that mAbs bind to and cross-link tumor targets, eliciting antibody- dependent cell-mediated cytotoxicity (ADCC), activating complement dependent cytotoxicity (CDC), and/or directly inducing tumor cell apoptosis.3



Monoclonal Antibodies Targeting the Bone Marrow-Stromal Cell Microenvironment

Anti-CS1

Elotuzumab is a humanized monoclonal IgG1 antibody directed against human CS1, a cell surface glycoprotein that is present on plasma cells and may also be expressed in NK and CD8+ T cells, belonging to the immunoglobulin gene superfamily.4 The majority of MM cell lines (97%) highly express CS1, which has been shown to mediate tumor cell adhesion, growth and proliferation.5 In vitro studies have shown that elotuzumab significantly inhibits myeloma cell binding to bone marrow stromal cells (BM- SCs) and induces ADCC.6,7

In a phase I dose-finding study of elotuzumab mono- therapy, no objective responses were observed, although 26.5% achieved stable disease (SD).8 The most common adverse events (AEs) were cough, headache, back pain, fever, and chills. In the relapsed setting, treatment with elotozumab in combination with lenalidomide and dexamethasone achieved an 80% overall response rate (ORR; partial response or better).9 A phase III registration study comparing lenalidomide and dexamethasone with and without elotuzumab in relapsed MM patients has just been completed.

Anti-CD40 and CD40L

CD40 is a transmembrane glycoprotein involved in B-cell activation, differentiation, and the formation of germinal centers.10 It is normally expressed on B cells, dendritic cells, and is highly expressed in human malignant plasma cells. In the presence of different cytokines (IL-4 and IL-10), the activation through CD40 or CD40-L can initiate B-cell growth and differentiation.11,12 CD40/CD40-L signaling reduces tumor cell proliferation and survival and may disrupt the protective immune state and stimulate immune-mediated antitumor activity in MM.13

Dacetuzumab (SGN-40) is a humanized agonistic IgG1 mAb with murine complementarity-determining regions (CDRs) which targets CD40. Preclinical studies observed that SGN0-40 induces tumor cell death in MM via breaking CD40/CD40-L interactions and activating NK-cell-me- diated ADCC.14,15 The first phase I study in recurrent or refractory MM patients with high disease burden did not show any objective responses, although SD was observed in 20%. There are ongoing phase I studies of SGN-40 in combination with lenalidomide and bortezomib.

Lucatumumab (HCD122, formerly CHIR-12.12) is a fully human, recombinant IgG1 isotype CD40L antagonist.16 It inhibits CD40/CD40-L dependent proliferation and survival and stimulates ADCC.17 In a phase I study of relapsed/ refractory MM patients, 12 of 28 (46%) achieved SD with a median duration of 61 days.18 Common AEs were infusion reactions, thrombocytopenia, and increased alanine ami- notransferase and lipase.

Monoclonal Antibodies Targeting Tumor Cells

Anti-CD138


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