Development of Effective Siglec-9 Antibodies Against Cancer

Purpose of Review This study aims to review state-of-the-art advances in Siglec-9-directed antibodies and to highlight specific aspects of Siglec-9 antibodies that are suitable to mount anti-tumor immunity. Recent Findings Controversies surrounding studies on Siglec-9 antibodies can confound future studies. In this review, we have highlighted some controversies, explained the distinction between Siglec-9 agonistic and antagonistic (endocytic) antibodies, and discussed their suitability in sustaining anti-tumor immunity. Summary Siglec-9 is an immune checkpoint target and an immunoinhibitory receptor that can engage either sialic acid ligands or agonistic antibodies. Through Siglec-9 sialic acid interactions, activated immunoreceptor tyrosine-based inhibitory signaling of the immune cells can lead to unfavorable immunosuppression. To overcome tumor-related immunosuppression, different types of Siglec-9 antibody blockade need to be developed. However, whether a Siglec-9-directed antibody is agonistic or antagonistic is probably affinity-dependent and not epitope-dependent. Additionally, unlike immune-modulatory antibodies such as agonistic antibodies (OX40, CD28, ICOS, and 4-1BB) or Fc-inert antibodies (PD1 and PD-L1) directed against cancer cells, the nature of antagonistic Siglec-9 antibodies is more suitable to enhance anti-tumor immunity and will be discussed.