901-03 - DEVELOPMENT OF BRB-002, A NOVEL NEXT-GENERATION ANTI-CD47 MOLECULE, FOR ATHEROSCLEROTIC CARDIOVASCULAR DISEASE

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Author Block: B Alexander Yi, Pierre Signore, Kevin Paavola, Ann M. Marseilles, Sharline Chen, RUI YUN, Andrew Morrison, Lili Adams, Brittany Winner, Nicholas Leeper, Vijay Bhargava, Sharon Crugnale, Pavan Cheruvu, Craig T. Basson, Bitterroot Bio, Palo Alto, CA, USA, Stanford University, Palo Alto, CA, USA
Background: Atherosclerosis is characterized by the deposition of lipoproteins in the vessel wall leading to inflammatory changes and the accumulation of cellular debris at discrete sites to form atherosclerotic lesions. The cell surface marker CD47 has been shown to be upregulated in atherosclerotic lesions. CD47 acts as a ‘don’t eat me’ signal that prevents the efficient clearance of cellular debris by binding to its cognate receptor, SIRPα, on macrophages—a process referred to as ‘efferocytosis’. Dysregulated CD47, therefore, may contribute to the expansion of atherosclerotic lesions by inhibiting efferocytosis.
Methods: We report the preclinical development of BRB-002, a novel next-generation recombinant Fc fusion protein comprised of a modified version of the N-terminal CD47-binding domain of SIRPα with increased affinity for CD47 fused to a modified human IgG4 Fc domain.
Results: In in vitro studies, BRB-002 bound to CD47 from multiple species with high affinity, antagonized the binding of SIRPα to CD47 on cells, and promoted phagocytosis of target cells by macrophages. BRB-002 was engineered to have an inactive Fc to minimize Fc-dependent effector functions; therefore, BRB-002 was demonstrated to have minimal antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC). BRB-002 also did not induce hemagglutination in vitro and had minimal effects on red blood cell parameters in rodents and non-human primates in vivo. Administration of BRB-002 resulted in a dose-dependent and sustained prolongation of CD47 receptor occupancy in animal models. In atheroprone apolipoprotein E-deficient mice, CD47 blockade significantly reduced the development of atherosclerotic plaque burden as well as inflammatory lesion size by up to 40-50%.
Conclusion: These results suggest that CD47 blockade has potential as a novel therapy for atherosclerosis. Based on these observations, a first-in-man study of subcutaneously administered BRB-002 is currently being investigated in an ongoing phase 1 clinical trial and results will be presented.