Antibody-Drug Conjugates

The advantages of mAb specificity have also been exploited in the development of ADCs, which have begun to show great potential, specifically as alternative cancer treatments. ADCs are a class of anticancer biopharmaceutical drug composed of a single mAb linked via a stable chemical linker to a varying number of biologically active cytotoxic small-molecule drugs [8, 55]. The high binding specificity of mAbs and their targeted receptors enables ADCs to be precise and effective delivery systems of the cytotoxins directly to the cancerous cells. In vivo, ADCs are recognized and bind to the receptors on the surface of the targeted cell. This then can lead to the internalization of the ADC where lysosomal digestion occurs, enabling the release of the cytotoxic drug, which consequently kills the target cancer cell [56]. Currently two ADCs are approved by the Food and Drug Administration (FDA): brentuximab vedotin (Adcetris® [Seattle Genetics, Inc.]) and ado-trastuzumab emtansine (Kadcyla® [Genentech, Inc.]). But with over 45 still involved in clinical trials and over 160 within preclinical trials [57], ADCs are likely to dominate a new generation of oncology therapeutics.

There are various conjugation methods applied to the covalent linking of the cytotoxic drug to the mAb, currently including three main strategies:

  • 1) Acylation of lysines [58]. Attachment of the cytotoxic drugs occurs through the e-amine group of lysine.
  • 2) Alkylation of genetically engineered cysteines [59]. Attachment to the thiol side chain of cysteine. The primary sequence of the antibody is mutated by the introduction of unpaired cysteine residues into the HC where they will not form inter- or intrachain disulfide bridges. Unpaired cysteine residues are then conjugated with the cytotoxic drug.
  • 3) Alkylation of cysteine residues generated by the reduction of existing interchain disulfide bonds [60]. The interchain disulfide bridges are partially reduced prior to the conjugation reaction. This results in a mixture of ADCs with drug loading ranging from zero to eight as shown in Figure 10.3.

One of the most important properties of an ADC is the average number of drug molecules attached [61, 62]. This determines the amount of cytotoxic drug being delivered to the tumor cells (the “payload”), which in turn affects the potency, safety, and efficacy of the ADC [63]. The drug component is typically a hydrophobic small drug molecule conjugated to exposed regions of the mAb. For cysteine-linked drugs, conjugates with zero, two, four, six, and eight cytotoxic payloads are observed typically resulting in an average DAR of four.

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