New Anti-CD20 Monoclonal Antibodies for the Treatment of B-Cell Lymphoid Malignancies

Abstract

Over the last few years, new generations of anti-CD20 monoclonal antibodies (mAbs) have been developed for potential benefits over the classical, first-generation mAb rituximab. Compared with rituximab, new mAbs have enhanced antitumor activity resulting from increased complement-dependent cytotoxicity (CDC) and/or antibody-dependent cellular cytotoxicity (ADCC) and increased Fc binding affinity for the low-affinity variants of the FcγRIIIa receptor (CD16) on immune effector cells. The second-generation mAbs, which include ofatumumab, veltuzumab, and ocrelizumab, are humanized or fully human to reduce immunogenicity, but with an unmodified Fc region. Ofatumumab is a fully human anti-CD20 IgG1 mAb in clinical development for hematological malignancies and autoimmune diseases. Ofatumumab specifically recognizes an epitope encompassing both the small and large extracellular loops of CD20 molecule, and is more effective than rituximab at CDC induction and killing target cells. Veltuzumab (IMMU-106, hA20) is a humanized anti-CD20 mAb with complementarity-determining regions similar to rituximab. This antibody has enhanced binding avidities and a stronger effect on CDC compared with rituximab. Ocrelizumab is a humanized mAb with the potential for enhanced efficacy in lymphoid malignancies compared with rituximab due to increased binding affinity for the low-affinity variants of the FcγRIIIa receptor. The third-generation mAbs are also humanized mAbs, but in addition they have an engineered Fc to increase their binding affinity for the FcγRIIIa receptor. The third-generation mAbs include AME-133v, PRO131921 and GA-101. AME-133v (LY2469298) is a type I, humanized IgG1 mAb with enhanced affinity for FcγRIIIa receptor and an enhanced ADCC activity compared with rituximab. PRO131921 is a humanized anti-CD20 mAb engineered to have improved binding to FcγRIIIa and better ADCC compared with rituximab. GA-101 (RO5072759) is a fully humanized, type II, IgG1 mAb derived from humanization of the parental B-Ly1 mouse antibody and subsequent glycoengineering using GlycoMab® technology. GA-101 was designed for enhanced ADCC and superior direct cell-killing properties, in comparison with currently available type I antibodies. TRU-015 is a small modular immunopharmaceutical (SMIP) derived from key domains of an anti-CD20 antibody. TRU-015 represents a novel biological compound that retains Fc-mediated effector functions and is smaller than mAbs. In this article we review data on new anti-CD20 mAbs that are potentially useful in the treatment of lymphoid malignancies.

AACR Cancer Progress Report 2013

“…generation of CD20-targeted antibodies with enhanced ability to recruit immune cells and direct them to attack the cancer cells (126).…”

AACR Cancer Progress Report 2016

“…Two such therapeutic antibodies, ofatumumab (Arzerra) and rituximab (Rituxan), were approved by the FDA in October 2009 and February 2010, respectively. Although these two agents, when used in combination with traditional chemotherapies, significantly increase survival for many patients (85), a substantial number of patients have disease that does not respond to initial treatment or eventually becomes resistant to it (85,86). As a result, researchers began working to develop more effective CD20-targeted therapeutic antibodies.…”

Effector mechanisms of anti-CD20 monoclonal antibodies in B cell malignancies

“…Currently there are more than ten agents targeting CD20, which are clinically approved or in clinical testing (originally reviewed in 43,44,29,35,45 and listed here in Table 1, which is compiled from these references, updated and modified). Accordantly, there are a number of published studies aiming to identify the molecular basis of the exerted clinical effects.…”