The majority of multiple myeloma (MM) patients will initially respond to standard chemotherapy. However, eventually relapse of the disease, associated with a multi-drug resistant phenotype, contributes to poor clinical outcomes. Modulation Therapeutics is dedicated towards developing strategies for targeting cancers like MM that home or metastasize to the bone. Our current lead compound binds a CD44/VLA-4 complex and induces necrotic cell death. The in vivo efficacy of MTI-101 has been demonstrated using two in vivo myeloma models which consider the bone marrow microenvironment when evaluating tumor response. Our lead compound is a cyclic peptide which reduces concerns of proteolytic degradation. However, the efficacy of the compound may still be limited by a short circulating half-life often typical of peptide based therapies. The oveall goal of this proposal is to utilize antibody conjugation strategies designed to increase the therapeutic window of our lead compound. The first goal of this proposal is to determine whether conjugation of MTI-101 to a non-targeting antibody will increase the in vivo efficacy of the compound. The second goal of this proposal is to generate and evaluate a conjugate of MTI-101 and a CD138-targeting antibody to determine if we can increase specificity of the compound and thereby increase the therapeutic window of our lead compound.
Clinical outcomes strongly support the need for the development of novel strategies for the treatment of multiple myeloma. To this end this proposal will determine whether we can increase the efficacy of MTI-101 utilizing antibody conjugation strategies designed to increase specificity and circulating half-life.