Abstract

Immunotherapies especially targeted towards oncology, based on antibody-drug conjugates (ADCs) have recently been boosted by the US Food and Drug Administration approval of Adcetris to treat Hodgkin’s lymphoma and Kadcyla for metastatic breast cancer. The emphasis of this article is to provide an overview of the design of ADCs in order to examine their ability to find and kill tumour cells. A particular focus will be on the relationship between the cytotoxic drug, chemical linker and the type of monoclonal antibody (MAb) used to make up the components of the ADC. Furthermore, the article will conclude on a carbon-14 labelled linker strategy for ADCs to be utilised in absorption, distribution, metabolism and excretion (ADME) studies towards regulatory new drug approval requirements.

INTRODUCTION

In 2012, the US Food and Drug Administration (FDA) gave approval to 39 drugs and this was the highest number since the mid 1990s (1). According to market analysis, the outlook remains strong for at least 35 new drug approvals per year until 2016 (2). The next blockbuster drug discoveries may well emerge from a class of targeted cell based immunotherapeutics called antibody-drug conjugates (ADCs). These are being developed by biopharmaceutical companies as the next generation of cancer treatments (3).
The first antibody targeted therapy came in 1986 with the FDA approval of OKT3 to treat organ rejection. This involved the use of a murine IgG2a monoclonal antibody (MAb) to target the CD3 antigen, which is a membrane protein on the surface of T-cells (4). Further technologies produced a number of G-type immunoglobulins (IgG) to target oncological conditions: rituximab (chimeric human-murine IgG1 targeting CD20 antigen, non-Hodgkin’s lymphoma), trastuzumab (humanized IgG1 targeting HER2 antigen, breast cancer) and alemtuzumab (humanized IgG1 targeting CD52 antigen, chronic lymphocytic leukaemia). Others include bevacizumab (humanized ...