Potent Monoclonal Antibody Drug Conjugates

DESCRIPTION (provided by applicant): In light of the efficacy of several new clinically approved monoclonal antibodies (mAbs) for cancer therapy, there has been a resurgence of interest in their use for the delivery of cytotoxic drugs to tumor cells. Recent studies have identified critical parameters that must be addressed for therapeutic efficacy, including intracellular uptake of the mAb within target cells, use of potent and stable drugs for delivery, and incorporation of conditionally stable linkage systems that allow for the selective release of active drug. In our Phase I SBIR study, we addressed these issues, and the work led to the development of cAC1O-valine-citrulline- monomethylauristatin E (cAC1O-Val-Cit-MMAE), a conjugate composed of three elements: the cAC1O mAb that recognizes the CD30 antigen on lymphomas, the Val-Cit peptide linker that is cleaved from the drug by lysosomal enzymes, and the highly potent antimitotic agent, MMAE. The conjugate, which contained 8 drugs/mAb, was stable in plasma, released drug in the presence of cathepsin B, and induced cures and regressions of established tumors with unprecedented therapeutic windows. We subsequently found that these conjugates were prone to aggregation and had accelerated in vivo clearance, in contrast to equally efficacious conjugates containing only 4 drugs/mAb (cAC10-Val-Cit-MMAE4). However, the current procedure for producing cAC10-Val-Cit-MMAE4 leads to a complex mixture of conjugates with varying degrees of drug substitution at different positions on the mAb. The objective of the Phase II SBIR research is to establish an optimized form of cAC10-Val-Cit-MMAE4 in terms of in vitro potency and specificity, in vivo safety and efficacy, pharmacokinetics and biodistribution, product uniformity, and ease of production. This will be accomplished by exploring a variety of chemical conjugation strategies for the preparation of cAClOVal- Cit-MMAE4. In parallel, we will engineer cACIO with cysteine to serine replacements, thereby enabling the construction of conjugates with precisely defined sites and stoichiometries of drug attachment. These studies will lead to the identification of a highly optimized form of cAC10-Val-Cit-MMAE4 for clinical trials in humans with Hodgkin's disease, anaplastic large cell lymphoma, and cutaneous T-cell lymphoma.