Engineering Antibodies for Clinical Applications in Cancer

Abstract

The ‘magic bullet’ concept predicted over a century ago that antibodies would be used to target cancer therapy. Since then initial problems that were related to specificity, purity and immungenicity of antibody-based reagents have slowly been overcome due to developments in technology and increased knowledge. As a result, antibodies are in use for many clinical applications and now comprise the second largest category of medicines in clinical development after vaccines. For antibody-based cancer therapeutics the last 20 years have met with an explosion of knowledge about the biology of the disease and potential targets as well as new technology which allows cloning and manipulation of multifunctional antibody-based molecules. However, the focus still remains on developing therapeutics that will have potential for treating cancer in people and this is efficiently assessed in mechanistic clinical trials that feed back to the laboratory for further development. This review illustrates the mechanistic approach to making new molecules for antibody imaging and therapy of cancer. It is illustrated by examples of radioimmunotherapy and antibody-directed enzyme prodrug therapy developed by the authors.

Microdistribution of Targeted, Fluorescently Labeled Anti–Carcinoembryonic Antigen Antibody in Metastatic Colorectal Cancer: Implications for Radioimmunotherapy

“…Monovalent antibodies have faster circulatory clearance and weaker antigen binding than IgGs, resulting in lower tumor uptake and therapeutic potential but reduced systemic toxicity. It has also been suggested that they have the ability to localize more rapidly into tumor deposits (37,38). However, our results show that there was no physical barrier to localization and penetration of IgG (MW 150 kDa) into and through hepatic tumor deposits of all sizes.…”

Adenovirus Tumor Targeting and Hepatic Untargeting by a Coxsackie/Adenovirus Receptor Ectodomain Anti–Carcinoembryonic Antigen Bispecific Adapter

“…Bispecific adapters with a CEA-binding domain should untarget adenovirus vectors from normal tissues and retarget them to CEA-positive tumors. MFE-23, a single-chain antibody with high affinity for CEA, is currently in phase I studies both as an imaging agent for radioimmunoguided surgery and as a tumor-targeting agent for antibody-directed enzyme prodrug therapy (20)(21)(22). To retarget CEA-positive cells, MFE-23 has been fused to sCAR to form sCAR-MFE, a bispecific transductional reagent.…”

Avidity-Mediated Enhancement of In vivo Tumor Targeting by Single-Chain Fv Dimers

“…Antibody engineering permits the design of new antibodybased proteins that can potentially address the shortcomings of intact antibodies as cancer therapeutics (1). One approach has been to produce the minimal antibody binding site in the form of a single-chain Fv (sFv), comprising the heavy and light chain variable domains of an antibody, joined by an appropriate linker peptide (2,3).…”