Breaking the immunogenicity barrier: strategies for therapeutic antibody discovery in canine and feline medicine

Therapeutic monoclonal antibodies are increasingly applied in canine and feline medicine; however, immunogenicity remains a major barrier to their clinical translation. Here, we summarize recent research advances in discovery strategies for low-immunogenicity antibodies in dogs and cats. We outline major technical platforms spanning from traditional murine antibodies to fully canine and feline-derived natural antibodies, including engineering of murine antibodies, phage display, single B-cell antibody technology, and high-throughput sequencing combined with emerging computational approaches. Emphasis is placed on the principles, advantages, and limitations of these strategies for mitigating anti-drug antibody (ADA) responses. Emerging technologies such as nanobody technology and transgenic mouse platforms are also introduced. A foundational constraint across these platforms is the limited annotation of canine and feline immunoglobulin germline genes. Other major challenges include species-specific production bottlenecks, the lack of unified standards for ADA detection, and the limited indication scope of approved drugs. Finally, future directions for developing low-immunogenicity therapeutic antibodies for companion animals are proposed, aiming to provide strategic insights for the rational development and clinical translation of such antibodies.