Linked-in: design and efficacy of antibody drug conjugates in oncology

Abstract

The use of antibody drug conjugates (ADCs) as targeted chemotherapies has successfully entered clinical practice and holds great promise. ADCs consist of an antibody and toxin-drug combined together via a chemical linker. While the antibody and drug are of vital importance in the direct elimination of cancer cells, more advanced linker technology was instrumental in the delivery of more potent drugs with fewer side effects. Here, we discuss the preclinical experience as well as clinical trials, with a specific emphasis on the clinical outcomes and side effects, in addition to linker strategies for five different ADCs, in order to describe different approaches in the development of this new class of anticancer agents. Brentuximab vedotin is approved for use in Hodgkin's lymphoma and Trastuzumab emtansine is approved for breast cancer. Combotox, Inotuzumab Ozogamicin, and Moxetumomab Pasudotox are in various stages of clinical development and are showing significant efficacy in lymphoid malignancies. These ADCs illustrate the promise and future potential of targeted therapy for presently incurable malignancies.

Figure 1. Timeline delineating the evolution of antibody-drug conjugate discovery and therapy in cancer therapeutics [3-6]

ADC: Antibody-drug conjugate, mAb: Monoclonal antibody, DLBCL: Diffuse large B cell lymphoma, DD: Denileukin Difitox, CTCL: Cutaneous T cell lymphoma, GO: Gentuzumab Ozogamicin, AML: Acute myeloid leukemia, r/r: relapsed and/or refractory, HL: Hodgkin's lymphoma, sALCL: Systemic anaplastic large-cell lymphoma, FDA: Food and Drug Administration, Her2: Human Epidermal Growth Factor Receptor 2, MBC: Metastatic breast cancer.

Figure 2. Composition and mode of action of antibody-drug-conjugates (ADC)

A) An ADC is composed of a monoclonal antibody directed against a specific epitope on a target cell. A cytotoxic compound is attached to the antibody via a linker. B) Once administered, the antibody component of the ADC binds to the targeted cell receptor, which enables the ADC to be internalized (usually via endocytosis) and subsequently degraded. The released toxin causes cell death via various mechanisms depending on the toxin, such as DNA damage or inhibiting protein translation.