Patent ID: 8580928

Claim:
A method of making an altered antibody comprising a heavy chain variable domain (VH) and a light chain variable domain (VL) comprising a first step of incorporating six non-human hypervariable regions (HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3) obtained from a non-human parent antibody into VH and VL acceptor human frameworks, respectively, thereby making a direct hypervariable region-grafted antibody, wherein the direct hypervariable region-grafted antibody has an antigen binding affinity less than the parent antibody, and comprising a further step of randomizing one or more amino acids in one or more of the non-human hypervariable regions wherein the one or more amino acids maintain a sequence bias towards the sequence of the incorporated non-human hypervariable region and wherein the randomizing step comprises the codon RGC for position 49 of HVR-H2 and the codon ARA for position 94 of HVR -H3, wherein the numbering is according to Kabat, without modifying the VH or VL acceptor human framework sequence, and selecting an altered antibody with restored or improved binding affinity (K d ) compared to the parent antibody, and wherein the restored or improved binding affinity has a value of no more than about 5 ×10 −7 M.