IND-enabling studies for eCD4-Ig as a long-acting recombinant protein therapeutic

ABSTRACT This FastTrack SBIR grant will support pre-clinical IND-enabling studies for recombinant eCD4-Ig protein, ahead of a first-in-human (FIH) Phase 1 clinical trial. eCD4-Ig is an antibody-like therapeutic for HIV consisting of parts of HIV’s receptor and coreceptors fused to the constant Fc region of an antibody. Due to being comprised of parts of HIV’s receptor and coreceptors, eCD4-Ig recognizes 100% of HIV isolates and cannot be escaped without HIV sacrificing its ability to bind its receptor and coreceptors. The eCD4-Ig protein we are developing has its effector function enhanced through afucosylation. Our Target Product Profile (TPP) for eCD4-Ig is a long-acting recombinant protein therapeutic that can be dosed quarterly (i.e., every 3 months) by subcutaneous injection as part of a long-acting combination regimen. Prior to a Phase 1 clinical trial, a necessary milestone is the submission of an Investigational New Drug (IND) application to the FDA. Here, we propose the preclinical IND-enabling studies that will support that Phase 1 clinical trial. In Phase I of this SBIR grant, we will conduct the in vitro assays required for IND application submission (tissue cross- reactivity, and immunotoxicity using human peripheral blood cells), and conduct a pre-IND meeting with the FDA. In Phase II of this grant, we will conduct a definitive GLP toxicology study in macaques. The study will assess changes in leukocyte and lymphocyte populations, body weight, food consumption, clinical signs, clinical chemistries, coagulation, urinalysis, toxicokinetics, anti-drug antibodies (ADAs), and histopathology. Safety pharmacology endpoints will include cardiotoxicity, respiratory toxicity, and central nervous system (CNS) toxicity. Doses for the study will be set to provide a 10x safety margin. This definitive GLP toxicology study is critical to proceed with a Phase 1 clinical trial. Completion of these studies will allow us to submit an IND application and bring eCD4-Ig into the clinic.