Antibody-Drug Conjugates for Cancer Therapy

Abstract

Antibody-drug conjugates (ADCs) are novel drugs that exploit the specificity of a monoclonal antibody (mAb) to reach target antigens expressed on cancer cells for the delivery of a potent cytotoxic payload. ADCs provide a unique opportunity to deliver drugs to tumor cells while minimizing toxicity to normal tissue, achieving wider therapeutic windows and enhanced pharmacokinetic/pharmacodynamic properties. To date, nine ADCs have been approved by the FDA and more than 80 ADCs are under clinical development worldwide. In this paper, we provide an overview of the biology and chemistry of each component of ADC design. We briefly discuss the clinical experience with approved ADCs and the various pathways involved in ADC resistance. We conclude with perspectives about the future development of the next generations of ADCs, including the role of molecular imaging in drug development.

Keywords: ADC; antibody–drug conjugate; cytotoxic payload; linkers, cancer; molecular imaging.; monoclonal antibody.

Figure 1

Antibody–drug conjugate structure.

Figure 2

Mechanism of action: (A) binding of ADC therapy to target cell surface antigen; (B) the antibody–drug conjugate undergoes receptor-mediated endocytosis; (C) the antigen–antibody–drug complex is delivered into the lysosomal compartment; (D) degradation of the antigen–antibody–drug complex occurs in an acidic and proteolytic enzyme-rich environment, resulting in the intracellular release of the drug; (E) intracellular release of the cytotoxic compound, resulting in cell death.

Figure 3

Mechanism of resistance: (A) impaired binding of the ADC to the target antigen by antigen downregulation, loss of antigen expression or mutations in the antigen; (B) defects in the internalization pathway and reduced cell surface trafficking; (C) impaired degradation of ADCs in lysosomes due to reduced lysosomal proteolytic or acidification function or loss of lysosomal transporter expression inhibiting the release of cytotoxic payload lysosomes to the cytoplasm; (D) cytoplasmic factors, e.g., aberrant polo-like kinase 1 activity preventing mitotic arrest or due to defective cyclin B1 induction; (E) the overexpression of drug efflux transporters; (F) dysregulation in the apoptotic pathway through the deficient activity of proapoptotic proteins Bak and Bax or the overexpression of antiapoptotic proteins BCl-2 and Bcl-x.

Figure 4

Representative biodistribution pattern of ¹¹¹In-CMD-193. Anterior whole-body γ camera images in patient 106 (1.0 mg/m2 dose cohort) following infusion are shown for day 1 (A), day 3 (B), and day 8 (C). Following infusion of ¹¹¹In-CMD-193, there was initial blood pooling, followed by markedly increased hepatic uptake by day 2 that persisted to day 8. No tumor uptake was apparent in the whole-body γ camera images (arrow) or SPECT (D). (E), corresponding CT scan shows the large hepatic metastasis, also evident in (F), coregistered SPECT/CT scan. Reprinted from the phase I biodistribution and pharmacokinetic study of Lewis Y-targeting immunoconjugate CMD-193 in patients with advanced epithelial cancers [186].