Project Summary
Therapeutic antibodies against tumor targets have become standard therapeutic approach in oncology and have
significantly improved clinical outcomes in liquid and solid tumors. In addition, therapeutic antibodies against immune
checkpoint receptors have shown a great therapeutic potential in oncology when administered alone and in combination.
However, adverse events related to presence of specific targets in normal tissues, especially in therapies combining two or
more therapeutic antibodies, can limit dosing and thus efficacy of therapies, as well as prevent potential targets from being
tested in clinical trials. Thus, a technology restricting therapeutic action to tumor sites would have a major impact on
clinical efficacy of antibody therapeutics. ScalmiBio proposes to develop universal platform for converting any
therapeutic antibody into activatable prodrug. Our technology acts to minimize interaction of an antibody therapeutic
with normal tissue, and maximizes its target binding capability within tumor. We achieve this by exploiting tumor's own
deregulated feature, activated proteases. Our technology thus allows antibody therapeutics to be activated in tumors by
specific tumor present proteases. The goals of this project are 1) develop a novel technology that turns any therapeutic
antibody into prodrug activated by tumor specific proteases and 2) convert an existing anti-CTLA4 therapeutic antibody
into anti-CTLA4 antibody prodrug. In this 1-year feasibility study we will focus on: First, optimizing our universal
shield which blocks interaction with target in normal tissues to generate anti-CTLA4 antibody prodrug, a validated target
of great therapeutic potential in immuno-oncology. Second, design, optimize, and experimentally validate protease
substrates for tumor specific therapeutic antibody activation. Protease substrates will be optimized for maximal cleavage
in tumor tissues and minimal cleavage in serum, using mass spectrometry assay. Our collaborator, Omix Technologies has
innovated chromatographic separations and mass spectrometry based data acquisition to develop high-throughput
proteomics platform. Their methodology enables analysis of highly powered sample sets in a time- and cost-efficient
manner. Third, our technology and protease substrates will be validated in-vivo in mouse colon carcinoma syngeneic
mouse model sensitive to anti-CTLA4 immunotherapy. ScalmiBio's technology platform will provide several benefits
over typical antibody therapeutic: 1) minimize unwanted side-effects of antibody therapeutics 2) unlock potential of new
targets 3) result in more predictable pharmacokinetics.