Development of antibody-based therapeutics for oncology indications

Abstract

Monoclonal antibodies have emerged as novel oncology therapeutics. These biologics exert anticancer effects via a variety of mechanisms of action including modulating the function of key regulatory molecules and signaling pathways of tumor cells such as blocking growth factor/receptor interaction and/or down-regulating expression of oncogenic proteins (e.g., growth factor receptors) on the cell surface; recruiting effector mechanisms of the immune system, such as antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity; as a targeting device in immnuoconjugates; and other mechanisms such as anti-idiotype, catalytic antibodies, or antibodies that modulate patient's immune responses to tumors. In this review, we focus on the research and development experience of four such representative antibody therapeutics, rituximab (Rituxan s ), trastuzumab (Herceptin s ), cetuximab (Erbitux s ), and bevacizumab (Avastin s ), approved for treating non-Hodgkin's lymphoma, metastatic breast cancer, and colorectal cancer, respectively. The biology behind each antibody target, their proposed mechanisms of action, as well as preclinical and clinical development of these antibodies are the topics of this article. Experience drawn from the development process of these four antibodies is instrumental for ongoing and future antibody development activities. In addition, perspective views on challenges and opportunities of oncology antibody therapeutics are presented. Drug Dev. Res. 67: 699-728, 2006.

Next generation of antibody therapy for cancer

“…In combination with cytotoxics or radiation therapy, these mAbs have delivered significant clinical improvements in treating lymphoma [rituximab (Rituxan)], breast cancer [trastuzumab (Herceptin)], colorectal cancer [bevacizumab (Avastin), cetuximab (Erbitux), and panitumumab (Vectibix)], non–small cell lung cancer (NSCLC) [bevacizumab (Avastin)], and squamous cell cancer of the head and neck [cetuximab (Erbitux)], and are expanding into broader indications. However, clinical benefits are often limited to transient tumor responses seen only in a fraction of patients with incremental improvements in progression-free survival (PFS) and overall survival (OS) [9] . New approaches to further improve the efficacy of these mAb therapies include (a) selecting patients who may derive the most benefit based on the molecular characteristics of their tumors; (b) improving biodistribution to effectively deliver mAbs to susceptible tumor cells to achieve maximal target and pathway inhibition; (c) optimizing antibody immune effector mechanisms such as complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC); (d) molecular engineering of new antibody formats, for example, bispecific antibody, antibody-drug conjugate, and Fc modification for prolonged in vivo half-life [10] .…”