CUMAb

CUMAb is a method for antibody humanization using Rosetta and human V-genes and J-genes. Ref (1)

Details

• Workflow:
  1. Starts from structure (or model) of animal Fv
  2. All FW regions replaced with human sequence
  3. FW encoded by V-gene and J-gene (Somatic hypermutation); D-gene in CDRH3 only, and can therefore be ignored
  4. This leads to 63,180 combinations with kappa subtype and 48,600 with lambda subtype light chains
  5. Ignores sequences with glycosylation sites and three or more cysteines
  6. In total, over 20,000 human Framework region sequences
  7. Relax w/ grafted CDRs; w/ antigen remaining fixed
  8. Eliminate designs that cause CDRs to deviate by more than 0.5 A RMSD, unless a computational model is used
  9. Cluster by V-gene subgroup
• Able to find non-obvious V/J-gene combinations for grafting of CDRs; four of five test cases did not use human equivalent of starting genes

See also

• Humanization can destabilize antibodies

1.

Tennenhouse A, Khmelnitsky L, Khalaila R, Yeshaya N, Noronha A, Lindzen M, et al. Computational optimization of antibody humanness and stability by systematic energy-based ranking. Nature Biomedical Engineering. 2023;8(1):30–44. Available from: https://doi.org/10.1038/s41551-023-01079-1