24 - Antibody-targeted therapy

Summary

Introduction

Since Köhler and Milstein first demonstrated that monoclonal antibodies (MoAb) directed against human differentiation antigens could be generated from hybridomas, which made large-scale production of MoAbs possible, there has been the expectation that these reagents would be used to treat hematologic malignancies. Subsequently, it was reported that fragments of antibody variable domains (Fv) could be linked together to make recombinant proteins capable of antigen binding. Methodologies in antibody engineering have since been developed to produce MoAbs and their fragments for clinical use and to generate constructs and conjugates with improved stability, more favorable pharmacokinetic profiles, increased affinity, enhanced effector functions, and reduced immunogenicity. This has facilitated the development of a large and growing number of MoAb-based agents that target antigens expressed by lymphohematopoietic cells for study and treatment in humans (Table 24.1). Leukemias are in general excellent candidates for MoAb-based targeted therapies because some antigens expressed on the surface of malignant cells are relatively lineage restricted and have limited normal tissue distribution (reviewed in Ch. 4). Since the late 1990s, significant progress has been made in the clinical application of antibody-targeted therapies in specific subtypes of leukemias and lymphomas in adults, leading to US Food and Drug Administration (FDA) approval for some of these novel drugs (Table 24.1). Many of the available MoAb-based agents that target lymphohematopoietic cell surface antigens have relevance to childhood leukemias, although at the time of writing this edition, only a small number of pediatric clinical trials have been conducted (reviewed in detail below). These studies offer proof of principle that MoAb-based therapeutics have the potential to overcome leukemia cell resistance to standard therapies and have relatively low risk of non-specific toxicities.