Making New Strides with Antibody Drug Conjugates

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Making New Strides with Antibody Drug Conjugates
Making New Strides with Antibody Drug Conjugates

Technology advancements over the past few decades have been astonishing. From playing Space Invaders on a grainy black-and-white television to acting out virtual scenarios with real-life graphics in video games played on high-definition screens, technology has reshaped daily life.

Likewise in the medical field, some therapies that were merely theoretical in the past are today being used to treat patients today, and with striking efficiency. One example of this is in the field of biologic therapeutics, more specifically, in the cancer-fighting capabilities of antibody-drug conjugates (ADCs).

The ADC is making a comeback from its initial entry as a chemotherapeutic agent over a decade ago.  This drug class is on the verge of living up to its great promise as an effective targeted treatment option for a variety of cancers. The concept behind the ADC is rather simple: to combine the strengths of the two most successful classes of therapeutic agents developed in oncology—antibodies for their selectivity, and cytotoxic drugs for their potency. The goal of this strategy is to increase the therapeutic index while limiting systemic exposure.1 One can think of the ADC as two drugs in one, consisting of three parts: a monoclonal antibody (mAb), a small-molecule toxin, and a linker molecule connecting the two.

The Monoclonal Antibody

Binding to its receptor, the traditional role of the monoclonal antibody is as a biological therapeutic agent that expresses its activities in a variety of ways, including by interfering with signal functions and by initiating a cytotoxic immune response (ie, antibody-dependent cellular toxicity [ADCC]).2,3 Being part of the ADC, has allowed for the role of the mAb to expand.  Here, the primary function is that of a vehicle. With such high affinity and selectivity for its antigen, the antibody is the perfect transporter to carry and deliver a payload of killer toxins directly into the cancer cell. 

With this precise delivery system, the ADC is designed to impose maximum damage to cancer cells, with minimum exposure to healthy ones. The process of selecting and engineering the right antibody to be part of the ADC is based on a number of factors including its abilities to remain in circulation long enough to gain adequate exposure; bind to a target antigen that is predominately (or exclusively) expressed by a cancer cell; and become internalized for intracellular delivery and activity of the small-molecule toxin.4,5  

The Small-Molecule Toxin

One huge advantage of the ADC compared with conventional chemotherapy is its ability to carry and deliver an otherwise intolerable, highly potent cytotoxin. Linked strongly to their antibody, these powerful toxins remain inactive before they become internalized as part of an ADC-antigen complex through a process known as receptor-mediated endocytosis.4 By remaining inactive until they are inside the cell, the ADC can be engineered with the most effective agents suitable for a specific antibody and tumor. Today, the majority of the small-molecule toxins being pursued fall into two major categories: those that cause damage to DNA, and those that interfere with tubulin polymerization.5

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