Method for generating avid-binding multispecific antibodies

A method for decreasing the binding affinity of a bispecific antibody comprising a first binding site specifically binding to a first cell-surface antigen and a second binding site specifically binding to a second cell-surface antigen, with said first and second antigen being on the same cell,

• wherein the first binding site is a mammalian or mammalianized binding site,
• wherein the first binding site is at least a pair of an immunoglobulin light chain variable domain and an immunoglobulin heavy chain variable domain,
• wherein the decreasing the binding affinity is a decreasing of the binding affinity of the first binding site to its antigen by mutating in the first binding site at least one amino acid residue at a position in the CDRs of the light chain variable domain or in the CDR1 or CDR2 of the heavy chain variable domain or in the two framework positions directly preceding the CDR3 in the heavy chain variable domain to an amino acid residue present at said position in a germline variable domain immunoglobulin amino acid sequence of the same mammalian species as that of the mammalian or mammalianized binding site,
• wherein the germline variable domain immunoglobulin amino acid sequence has the highest identity of all germline variable domain immunoglobulin amino acid sequences of the mammalian species to the respective light or heavy chain variable domain of the first binding site of the bispecific antibody, based on a sequence alignment of said all germline variable domain immunoglobulin amino acid sequences of the mammalian species to the respective light or heavy chain variable domain of the first binding site of the bispecific antibody, and
• wherein the mutated mammalian or mammalianized binding site is free of polyreactivity.