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By Venkata Kashyap Yellepeddi and Rakesh Gollen

Venkata Yellepeddi-finalRakesh GollenAntibody-drug conjugates (ADCs) belong to a new class of targeted cell immunotherapeutics mostly developed for the effective treatment of cancer. They represent the major hope in the war against cancer and a substantial step towards personalized medicine.

An ADC comprises two components: a monoclonal antibody (mAb) and a small amount of highly potent cytotoxic drug linked to the antibody. The mAb component binds to the target antigen on the surface of the tumor cell (e.g., CD40, CD21, CD72, HER2, etc). The ADC-antigen complex is then internalized into the cell by endocytosis and by virtue of intracellular conditions (gluthatione, acidic pH, etc.), the ADC gets cleaved to release the cytotoxic drug, which then binds to its molecular target to elicit the required pharmacological effects. The first Food and Drug Administration (FDA) approved antibody-drug conjugate was the CD33 antigen targeted ADC Mylotarg (gemtuzumab ozogamicin) for the treatment of acute myeloid leukemia. However, due to lack of target-dependence and narrow therapeutic index, this ADC was withdrawn from the U.S. market.

The major breakthrough in ADCs was seen in 2011 with accelerated approval of Adcetris (brentuximab vedotin, SGN-35) to treat Hodgkin lymphoma and systematic anaplastic large-cell lymphoma. In February 2013, another ADC success was witnessed by FDA approval of Kadcyla (trastuzumab emtansine, T-DM1) for the treatment of metastatic breast cancer. Anticancer agents target a single specific mutation or gene amplification and restore pathologic cell proliferation, survival, growth, apoptosis, invasion, angiogenesis, metabolism, and metastasis by inhibiting deregulated single-cellular signaling pathways. Until now, almost 35 anticancer targeted drugs have been approved by FDA, and more than 350 more candidates are in various stages of development (preclinical and clinical), aiming at the discovery of more effective therapies. It is projected that the global market for ADCs will reach $2.8 billion by 2018.

The crucial aspect of ADC manufacturing involves choosing the right linker to attach mAb to the cytotoxic drug. Critical areas for ADC development include target antigen selection, adequate linker stability to overcome the hydrolytic environment before reaching the tumor and even after internalization into the tumor cells, and the ability of the linker to get cleaved efficiently to deliver the cytotoxic drug cargo. Current ADCs utilize linker technologies such as hydrazone and hydrazide moieties, disulfide linkers, and amide linkers. From a regulatory perspective, an ADC must be analyzed extensively to show that the cytotoxic drug has potent anti-tumor activity, the linker is stable enough to deliver ADC to target antigen, the mAb has high affinity and selectivity towards cellular target with low immunogenicity, and a lack of mAB process-related impurities such as virus and/or DNA. Future trends in ADCs include carbon-14 labelled ADCs for human micro-dosing AME (absorption-metabolism-excretion) studies to obtain critical information on cellular targets towards FDA drug approval, and development of radionuclide-antibody conjugates for cancer diagnosis and imaging.

ADC-based therapies provide an exciting opportunity in the field of biotherapeutics and targeted drug delivery. Their contribution toward personalized medicine for the treatment of cancer is significant, and with successful biopharmaceutical partnerships ADC platforms can lead to biotherapeutics with maximum efficacy and limited side effects.

Venkata Kashyap (Kash) Yellepeddi, B.Pharm., Ph.D., is an assistant professor of pharmaceutical sciences at the College of Pharmacy, Roseman University of Health Sciences, and an adjunct assistant professor at the University of Utah.
Rakesh Gollen is currently pursuing his Ph.D. from Long Island University, with a major in Drug Metabolism and Pharmacokinetics, under the supervision of David Taft, Ph.D. His research focus is on the predictions of pharmacokinetic parameters in special population, using the physiologically based pharmacokinetics modeling approach.