Engineering therapeutic monoclonal antibodies Summary: During last two decades, the chimerization and humanization of monoclonal antibodies (mAbs) have led to the approval of several for the treatment of cancer, autoimmune diseases, and transplant rejection. Additional approaches have been used to further improve their in vivo activity. These include combining them with other modalities such as chemotherapy and redesigning them for improved pharmacokinetics, effector function, and signaling activity. The latter has taken advantage of new insights emerging from an increased understanding of the cellular and molecular mechanisms that are involved in the interaction of immuno- globulin G with Fc receptors and complement as well as the negative signaling resulting from the hypercrosslinking of their target antigens. Hence, mAbs have been redesigned to include mutations in their Fc portions, thereby endowing them with enhanced or decreased effector functions and more desirable pharmacokinetic properties. Their valency has been increased to decrease their dissociation rate from cells and enhance their ability to induce apoptosis and cell cycle arrest. In this review we discuss these redesigned mAbs and current data concerning their evaluation both in vitro and in vivo . Keywords: monoclonal antibody, Fc, effector function, pharmacokinetics, tumors Introduction Since the early 1980s, monoclonal antibodies (mAbs) have made the transition from discovery to clinical practice. Several of these mAbs, alone, or attached to payloads, are being used for the treatment of cancer. The first mAb approved by the Food and Drug Administration (FDA) for human use was a murine anti-CD3 mAb, muromonab (OKT3), used for the treatment of organ transplant rejection (1). OKT3 provided the first lesson in the mAbs field, i.e. murine mAbs had a short half-life, robust immunogenicity, and suboptimal effector functions when used in humans. These problems were solved by converting mouse mAbs into human protein formats by genetic engineering. Between 1984 and 1988, both chimerization and humaniza- tion of mAbs were achieved (2–4). A chimeric mAb is designed to contain the variable regions of a mouse antibody and the constant regions of a human antibody, while in a humanized mAb, only the complementary determining re- gions (CDRs) are of murine origin. Fully human mAbs were Xiao-yun Liu à Laurentiu M. Pop à Ellen S. Vitetta Immunological Reviews 2008 Vol. 222: 9–27 Printed in Singapore. All rights reserved r 2008 The Authors Journal compilation r 2008 Blackwell Munksgaard Immunological Reviews 0105-2896 Authors’ address Xiao-yun Liu 1à , Laurentiu M. Pop 1à , Ellen S. Vitetta 1 , 1 The Cancer Immunobiology Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA. Correspondence to: Ellen S. Vitetta The Cancer Immunobiology Center University of Texas Southwestern Medical Center at Dallas 6000 Harry Hines Blvd NB9.210, Dallas, TX 75390-8576, USA Tel.: 214 648 1200 Fax: 214 648 1204 e-mail: ellen.vitetta@utsouthwestern.edu Acknowledgements The authors thank Dr Victor Ghetie, Allison Caroll, Lydia Wu, and Kelly Mapes for comments concerning the paper, and Ms Linda Berry for administrative assistance. à These authors contributed equally to this review. 9