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.