Therapeutic monoclonal antibodies in oncology

Abstract

The mainstay of systemic therapy for solid and haematological malignancies in the 20th century was chemotherapy. This approach has the drawbacks of toxicity to normal tissue, drug resistance and lack of efficacy. The demand for more effective and tolerable treatments has led to the development of novel therapeutic agents that specifically target the malignant cell. The hallmarks of malignant disease are self sufficiency in growth signals, insensitivity to growth inhibition, evasion of apoptosis, acquisition of limitless replicative potential, induction of angiogenesis and invasion and metastasis.1 All these processes are ultimately due to genetic defects which subsequently lead to the abrogation of normal cellular processes. Key to the development of targeted therapies is the ability to define the growth factors, transcription factors or receptors that phenotypically distinguish, in some way, the tumour from its normal counterpart. One class of novel agents that can specifically target and disrupt molecular pathways underlying tumorigenesis are the therapeutic monoclonal antibodies. Monoclonal antibodies are produced by a single clone of B-cells, and are monospecific and homogeneous. Since the original report on production of such antibodies, by Kohler and Milstein2 in 1975, a vast number have become available. Early developments in the cancer sphere were made in the academic sector, with the identification of tumour-associated antigens and immunization with tumours to produce novel monoclonal antibodies. Initially, the antibodies were created by fusing B cells from immunized mice with human lymphoma cells, thus creating murine monoclonal antibodies. A big disadvantage of these preparations was that human recipients developed antimouse antibodies, which led to allergic reactions and reduced the efficacy.3 However, application of recombinant DNA technology led to the development first of chimeric antibodies, then of partially humanized antibodies,4,5 and ultimately of fully humanized antibodies.6 Box 1 outlines the features of the different types in this progression. Radiochemistry and antibody engineering research were initially driven by the academic sector, followed by start-up biotech companies and subsequently larger pharmaceutical conglomerates. Whilst many of the antibodies were tested in the clinical setting—either unconjugated or more commonly as radioimmunoconjugates—very few (anti-CD20 being the first major exception) went on to be commercially developed. Box 1 Types of monoclonal antibody that have been developed Type of antibody Chimeric Chimeric antibodies are 65–90% human and consist of the constant or effector domain of the human antibody molecule combined with the murine variable regions (which bring about antigen recognition) by transgenic fusion of the immunoglobulin gene Partially humanized Partially humanized antibodies are about 95% human and consist of the complementarity determining regions of the murine antibody (which determine antibody specificity) and a limited number of structural aminoacids grafted onto a CDR-depleted human antibody backbone by recombinant technology Deimmunized Deimmunized antibodies have the immunogenic epitopes in the murine variable domains replaced with benign aminoacid sequences, resulting in a deimmunized variable domain. The deimmunized variable domains are linked genetically to human antibody constant domains Primatized Primatized antibodies have a chimeric antibody structure of human and monkey that is close to an exact copy of a human antibody Fully humanized Fully human antibodies have been developed by use of genetically engineered transgenic mice and advances in the generation of synthetic human antibody libraries At present, therapeutic monoclonal antibodies are being used in haematological and solid malignancies including non-Hodgkin's lymphoma, breast cancer and colorectal cancer. The mechanism of their antitumour effect is not precisely known but is thought to include complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity and blocking or steric hindrance of the function of the target antigen. This review focuses on current use in oncology but Table 1 lists some of the antibodies in clinical development. Table 1 A summary of monoclonal antibodies used in cancer medicine or in development