? Applied Research Project Our cell-depleting antibody resource has expanded greatly in antibody quantity, quality, and diversity over the past 15 years. We are now proposing to use a new applied research approach to refine our resource, by identifying genotypes associated with therapy effectiveness. Success in cell-depletion treatments is determined by the antibody?s ability to engage with its ligand and trigger effector mechanisms. When either of these functions is suboptimal the patient might present a partial or no depletion. In humans, differential response to therapeutic cell-depleting monoclonal antibodies has been associated with specific polymorphisms in Fc gamma receptors. Indeed, Fc receptors (FcR) and antibody target gene biomarkers are currently used to identify patients who are predicted to respond to the targeted agents. While most of our animals respond to cell-depletion treatments, it is often the case that one or two animals (~10%) in a given experiment will not have efficient depletion levels. Because the mechanisms underlying the lack of therapy success are undetermined, neither can the investigators pre-screen study animals nor can we design antibodies that overcome this barrier. For best use of our cell- depleting resources, therefore, we are proposing to identify genetic associations of target and immune effector genes with cell-depletion treatment success. Our preliminary data suggest a differential distribution of common FcR alleles in animals with inefficient vs efficient cell depletion. We will use a candidate gene case-control association study that is sufficiently powered (n= 220-250) to identify genetic markers that correlate with treatment outcomes. The identification of biomarkers that are predictive of efficacious depletion would have an immediate impact on our resource, by allowing researchers to screen animals prior to study or treatment initiation. Importantly, this information can be used to take corrective actions and improve treatment performance, by either excluding poor responders or modifying therapy regimens. During the course of the next cell-depleting program cycle, the genetic variant data will also be used to guide the design of broadly functional antibodies against common target variants. Finally, in the long term, this information will be used to design a new generation of rhesus antibodies with high affinity to commonly expressed FcRs. In summary, are proposing to identify relevant polymorphisms by sequencing genes encoding the target ligands of our antibodies or Fc receptors from animals with divergent cell depletion outcomes. This will improve our resource by 1) generating biomarkers associated with cell depleting therapy efficacy; 2) guiding the development of antibodies that will recognize most common target variants; and, in the long term, 3) lead to the development of a new generation of rhesus antibodies with a superior recognition by commonly expressed FcRs.
