Associate editor: B. TeicherMonoclonal antibody-based therapies in cancer: Advances and challenges
Introduction
Chemotherapy remains an important and widely used treatment option for many types of cancers, but the toxic side effects often limit optimal dosing of anticancer drugs, thus leading to disease relapse, development of drug resistance and poor quality of life of cancer patients. Since tumor cells share many common features with the normal cells, designing a drug that would selectively destroy cancer cells, bypassing normal healthy cells represents a major challenge of oncology drug development. The ‘magic bullet’ concept, envisioned by Paul Ehrlich over 100 years ago, led to a search for therapeutic modalities that could selectively target cancer cells. One possible strategy to overcome the collateral toxicity of conventional anticancer agents is to harness the power of “precision-guided” monoclonal antibodies (mAbs) that can deliver the drugs to the selectively-expressed or overexpressed antigens present on cell surface of malignant cells. The clinical success of anti-CD20 mAb (rituximab), the first approved unconjugated mAb for the treatment of cancer, has spurred considerable interest in the development of a number of actively pursued antibody (Ab)-based technologies, including immunotoxins (ITs), radioimmunotherapeutics (RITs), antibody-drug conjugates (ADCs) and immunoliposomes (ILs). However, despite the popularity of these modalities, the field still faces significant challenges in translating promising pre-clinical findings to positive outcomes in the clinic and hence largely relies on empiricism rather than defined principles to guide drug development. In this article, we focus on major advances and limitations in biological therapies including ADCs, ITs and ILs and also discuss important criteria to consider when developing these agents.
Section snippets
Antibody-drug conjugates
ADCs constitute a therapeutic modality in which a cytotoxic agent is chemically linked to an antibody (Ab) that recognizes a tumor-associated antigen (Fig. 1). The basic strategy underlying ADC technology is to combine the target selectivity of mAbs with the potency of cytotoxic agents, such as certain natural products and synthetic molecules, with the goal of generating therapeutic drugs that are highly efficacious but also safe. The ADC platform currently includes a growing repertoire of
Immunotoxins
Tumor-targeting ITs are chimeric molecules composed of a protein toxin moiety that is either chemically conjugated or genetically fused to mAbs or Ab fragments (Fig. 1). Initial efforts in IT field focused on chemical conjugation of IgGs or Fab′ fragments to variety of native toxins via disulfide or thioether linkages. Many 1st generation ITs however, suffered from major limitations, including serious side effects, lack of specificity, and immunogenicity. Eventually, toxin units were redesigned
Immunoliposomes
Since their discovery by Bangham et al. about 50 years ago (Bangham et al., 1965), liposomes have drawn a lot of interest as pharmaceutical carriers for drugs and genes. Classical liposomes, are made up of amphiphilic phospholipids and cholesterol, which, upon hydration, self-associate to form bilayers surrounding an aqueous interior. Hydrophilic drugs can be entrapped in the aqueous interior and hydrophobic drugs can be associated with the bilayer. Amphiphilic drugs that are weak bases or weak
Conclusions and future advances
Extensive pre-clinical knowledge and clinical expertise has accumulated over several decades in the field of mAbs and mAb-targeted therapies for oncology indications. Interestingly, most of the Ab-based delivery systems incorporating tumor-killing moieties such as ADCs, ITs and ILs follow similar design principles. Besides Ab construction and engineering, the following key factors should be considered when designing a successful agent: target expression and overall receptor biology,
Conflict of interest statement
No sources of funding were used to assist in the preparation of this article. All authors are full time employees of Pfizer Inc. The authors have no other conflicts of interest regarding the content of this article.
Acknowledgments
The authors would like to acknowledge the kind assistance of Drs. Russell Dushin and Fiona Mack in proof reading this manuscript.
References (217)
- et al.
Identification of the genes differentially expressed in human dendritic cell subsets by cDNA subtraction and microarray analysis
Blood
(2002) - et al.
Large unilamellar liposomes with low uptake into the reticuloendothelial system
FEBS Lett
(1987) - et al.
Liposomal drug delivery systems: from concept to clinical applications
Adv Drug Deliv Rev
(2013) - et al.
Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer
Cancer Lett
(2011) - et al.
Molecular mechanism of the lipid vesicle longevity in vivo
Biochim Biophys Acta
(1993) - et al.
Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study
Lancet
(2012) - et al.
Effective therapy of human lymphoma xenografts with a novel recombinant ribonuclease/anti-CD74 humanized IgG4 antibody immunotoxin
Blood
(2005) - et al.
Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies
Blood
(2004) - et al.
RNA N-glycosidase activity of ricin A-chain. Mechanism of action of the toxic lectin ricin on eukaryotic ribosomes
J Biol Chem
(1987) - et al.
A phase-I study of an anti-CD25 ricin A-chain immunotoxin (RFT5-SMPT-dgA) in patients with refractory Hodgkin's lymphoma
Blood
(1997)