G-Coupled Protein Receptors (GPCR) remain one of the most attractive but more challenging therapeutic targets for antibody discovery. Complement component 5a receptor 1 (C5aR1) is a GPCR of interest with potential therapeutic applications in immune-oncology and inflammation. This GPCR is involved with the complement cascade and in innate immunity. Stimulation of C5aR1 by its ligand, C5a, promotes tumorigenesis by suppressing T-cell mediated anti-tumor activity while blockade of C5aR signaling has been shown to attenuate tumor growth. In a combined approach with Macromoltek, we leverage Twist’s DNA synthesis and library assembly technology with structural-based machine learning to design a targeted anti-C5aR discovery library to identify several highly potent and selective lead antibodies against C5aR. Several of the candidates identified from this study are also shown to have functionally antagonistic effects on C5aR1-mediated signaling in cellbased assays. This work demonstrates how the combination of highly specific DNA synthesis, coupled with informed design, can be paired to successfully prosecute challenging targets for novel therapeutic discovery.