Project 3: Development of Novel Antibody Drug Conjugates for the Treatment of Osteosarcoma

PROJECT 3: ABSTRACT Strategies to reduce the morbidity and mortality from pediatric osteosarcoma (OS) are critically needed. 30 to 40% of OS patients recur after receiving highly toxic chemotherapy, In the past three decades, there have been no new therapies successfully developed for this cancer with. Antibody drug conjugates (ADCs), designed to specifically bring cancer drugs, known as payloads, to tumor cells while leaving normal cells unharmed, represent a promising strategy. Several ADCs have been FDA approved for a variety of cancers, but none for osteosarcoma. Thus, Project 3 will focus on the development and clinical translation of ADCs specific to surface proteins abundantly present in OS coupled to relevant payloads. Preliminary data provides compelling evidence that OS expresses readily available cell surface proteins which can serve as potential targets for therapies and could serve as epitopes for endogenous immune responses and immunotherapies. To clinically translate newly developed immunotherapies and targeted therapies more efficiently, determining which OS patients will or which patients will not respond to therapy is key for appropriate patient selection. Selecting which patients are likely to respond could be guided by the identification and validation of blood biomarkers. Recent biomarker studies have shown that exosomes, which are representative of and shed from tumor cells into the blood circulation, can provide useful information on tumor evolution, metastasis, and cancer recurrence and/or relapse risk. In the first aim of this work, studies of ADCs targeting cell adhesion molecule 1 (CADM1), a protein highly expressed in OS, will be performed in OS patient derived xenograft (PDX) models for payload optimization, understanding of emerging drug resistance, and as studies to enable IND filing. In the second aim we will develop bispecific antibodies (Bs)ADCs that target two different OS surface proteins. While the terminology bispecific usually refers to antibodies which lead to T cell engagement, in this case our goal is to combine two different antigen targets on one antibody to enhance affinity and specificity. Our intent is to focus on combining CADM1 and T-cell checkpoint ligand B7-homologue (B7H3), which is also known to be a highly relevant target in OS. These bispecific antibodies will be tested for efficacy as ADCs. In the third aim a phase 1/2 trial of an already developed ADC will be conducted in patients with osteosarcoma. In addition to evaluating the safety and preliminary efficacy of an B7H3-targeting ADC, this aim will also allow the development of an OS liquid biopsy approach using circulating exosomes to identify signatures predictive of response to treatments. Biospecimens obtained in this, trial as well as other acquired OS samples, will permit additional profiling of the cell surfaceome (both proteins and their post-translational modifications) to identify novel, preliminary OS surfaceome targets as well as explore drug resistance. It is expected that this work will significantly improve the lives of OS patients through the identification of effective and potentially less toxic therapies.