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Genetic Engineering & Biotechnology News | GENengnews.com | MAY 1, 2015 | 27 BIOPROCESSING die, they are simply replaced by new ones. The emergence of antibody-drug conjugates (ADCs) perfectly illustrates this point. Bioconjugation has been applied success- fully and commercially to all three major bio- logical product types: monoclonal antibodies, vaccines, and recombinant proteins. ADCs are of particular interest because of the precise targeting and long circulating half-life con- ferred by the antibody component, and the cytotoxic capabilities of the conjugated drug. With approximately 40 ADCs currently in development, one could say that therapeutic chimera has breathed new life into monoclo- nal antibodies. Developed by Catalent Biologics, the SMARTag™ platform for manufacturing ADCs incorporates the three major ADC components—monoclonal antibody, linker, and drug. "Each of these pieces must be carefully considered when designing an ADC to en- hance its overall in vitro and in vivo proper- ties," says Penelope M. Drake, Ph.D., biol- ogy group leader. The SMARTag site-specifc conjugation chemistry yields homogeneous, stable ADCs with strong antitumor effects, long half-lives, and reduced toxicity com- pared with conventional ADCs. SMARTag also affords the opportunity to explore structure-activity relationships sur- rounding payload and linker composition, according to Dr. Drake: "The conjugation chemistry is compatible with different classes of payloads and toxins with different modes of action, including tubulin disruptors and DNA alkylators." And the versatile chem- istry is compatible with cleavable and non- cleavable linker systems, as well as a variety of stable linker components. Dr. Drake cites work by Seattle Genetics demonstrating that the stoichiometry of drug loading signifcantly infuences a drug's pharmacokinetics, and with it effcacy and toxicity. It is now recognized that for some ADCs, a drug-antibody ratio (DAR) of 4 is more potent than a DAR of 2, and that 4 was comparably effective but better toler- ated than a DAR of 8. "It is therefore important to carefully consider DAR when designing an ADC to achieve optimal drug loading to maximize therapeutic index," Dr. Drake concludes. Control via New Chemistry Seattle Genetics' controlled conjugation strategies encompass several aspects of ADC manufacture and product control, includ- ing process consistency and robustness, and control of product quality. The goal of con- trolled or site-specifc conjugation is greater homogeneity of the ADC product. Essential to Seattle Genetics' ADC conju- gate technology are the stable linkers and syn- thetic cytotoxic agents. In preclinical models, the company's linkers are up to 10 times more stable in blood than conventional linkers. The lead cytotoxic agents are the auristatins, which constitute a class of microtubule-dis- ruptors. These agents include monomethyl auristatin E and monomethyl auristatin F. The auristatins are 100 to 1,000 times as potent as traditional chemotherapy drugs. Seattle Genet- ics is also investigating another ADC technol- ogy that uses an extremely potent cytotoxic agent, a pyrrolobenzodiazepine dimer. Because both linker and cytotoxic agents are synthetic, this ADC technology is readily scalable. According to the company, this rep- resents an improvement over natural prod- uct drugs which are more expensive to make. "The ADC supply chain is complex," com- ments Michael Sun, Ph.D., director of clinical manufacturing. "The manufacture of the anti- body and small molecule components require different production facilities and skill sets." Conjugation of components to produce an ADC presents another unique set of re- quirements related to the combination of bi- ologics and small molecules. Once the need for special safety protection (due to the high potency of the small molecule and the ADC) is factored in, the complexity of production facilities, each with its specialized capabili- ties, becomes apparent. "Coordinating the activities across the different parts of the supply chain can be dif- fcult," explains Dr. Sun. "And the total time required for production is quite a bit longer than for a typical biologic product." Achieving coordination becomes even more diffcult when a contract manufacturing organization (CMO) is involved. "A good synergistic strategy followed by innovative companies involves leveraging the depth of in-house process and analytical de- velopment with the manufacturing and high potency capability of CMOs," Dr. Sun con- tinues. Under such a strategy, process and analytical development is performed in-house, and technology is transferred to CMOs for manufacturing. "This keeps the expertise and subject matter experts in-house, where those assets are most valuable, for example, in regu- latory submissions and inspections, while out- sourcing manufacturing activities without the infrastructure investment." An ADC consists of a monoclonal antibody (mAb), a membrane-permeable payload, and a chemical linker (top). The variable region of the mAb (gray) is the region that binds to the cell surface antigen (bottom). Once the ADC is delivered (1), it binds (2) and is internalized via endocytosis (3). The ADC then trafcks to the lysosome (4), where lysosomal proteases degrade the ADC into its component parts. The small molecule drug payload is released into the cytoplasm (5) and accesses molecular targets, inducing cell death (6). Catalent Biologics Seattle Genetics' antibody-drug conjugate (ADC) technology employs a monoclonal antibody specific for a tumor-associated antigen, plus synthetic cytotoxic agents connected by stable linker systems (see the inset). These components are designed to securely bind the cytotoxic agent to the antibody and then release the agent within the targeted cell (see the main image).