Mitchell E. Reff, PhD, Kandasamy Hariharan, PhD, and Gary Braslawsky, PhD

Abstract and Introduction
Abstract
Background. The approval of monoclonal antibodies (MAbs) as antibody-targeted therapy in the management of patients with hematologic malignancies has led to new treatment options for this group of patients. The ability to target antibodies to novel functional receptors can increase their therapeutic efficacy.
Methods. The authors reviewed improvements in MAb design to enhance their effectiveness over the existing therapeutic MAb currently approved for treating hematologic malignancies.
Results. Three classes of therapeutic MAbs showing promise in human clinical trials for treatment of hematologic malignancies include unconjugated MAb, drug conjugates in which the antibody preferentially delivers a potent cytotoxic drug to the tumor, and radioactive immunotherapy in which the antibody delivers a sterilizing dose of radiation to the tumor.
Conclusions. A better appreciation of how MAbs are metabolized in the body and localized to tumors is resulting in the development of new antibody constructs with improved biodistribution profiles.

Introduction
The 1997 approval in the United States of rituximab (Rituxan), a recombinant chimeric anti-CD20 monoclonal antibody (MAb), for drug refractory lowgrade or follicular Betacell non-Hodgkin's lymphoma (NHL) has presented new treatment options for many patients using MAbs as therapeutic agents for hematologic malignancies. Since the approval of rituximab, the US Food and Drug Administration (FDA) has recently approved alemtuzumab (Campath-1H), a humanized rat antibody to CD52 for treatment of refractory chronic lymphocytic leukemia, and gemtuzumab ozogamicin (Mylotarg), a calicheamicin-conjugated humanized mouse anti-CD33 MAb for therapy of drug-refractory acute myeloid leukemia.^[1] Currently, the FDA has favorably examined the safety and efficacy of yttrium-90 (90Y)-labeled radioactive murine anti-CD20 MAb (Zevalin) for rituximab- and chemotherapy-refractory NHL and is also examining iodine-131 (131I)-labeled radioactive murine anti-CD20 (Bexxar) following multicenter phase III clinical trials.^[2]

Thus, three main classes of therapeutic MAbs have shown utility in human clinical trials for treatment of hematologic malignancies: (1) unconjugated MAb, in which the MAb either directly induces negative growth signal or apoptosis or indirectly activates host defense mechanisms to mediate antitumor activity, (2) drug conjugates in which the antibody preferentially delivers a potent cytotoxic drug to the tumor, thus decreasing the systemic toxicity normally associated with conventional drug therapy, and (3) radioactive immunotherapy in which the antibody delivers a sterilizing dose of radiation to the tumor.

Our recent understanding of how engaging functional receptors leads to tumor growth or death has increased the opportunity to target antibodies to novel functional receptors that can increase their therapeutic effectiveness. Our knowledge of antibody activation of host defense mechanisms permits modifications of antibodies to improve activation and enhance these functions. Furthermore, a better appreciation of how MAbs are metabolized in the body and localized to tumors is resulting in the generation of antibody constructs with improved biodistribution profiles. This review discusses improvements in MAb design to enhance their effectiveness over the existing therapeutic MAb currently approved for treatment of hematologic malignancies.

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Mitchell E. Reff, PhD, Kandasamy Hariharan, PhD, and Gary Braslawsky, PhD, from the Molecular Biology and Tumor Immunology Departments, IDEC Pharmaceuticals Corp, San Diego, California.

Cancer Control 9(2):152-166, 2002. © 2002 H. Lee Moffitt Cancer Center and Research Institute, Inc