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Generation of inhibitory monoclonal antibodies targeting matrix metalloproteinase-14 by motif grafting and CDR optimization.

ABSTRACT: Matrix metalloproteinase-14 (MMP-14) plays important roles in cancer metastasis, and the failures of broad-spectrum MMP compound inhibitors in clinical trials suggested selectivity is critical. By grafting an MMP-14 specific inhibition motif into complementarity determining region (CDR)-H3 of antibody scaffolds and optimizing other CDRs and the sequences that flank CDR-H3, we isolated a Fab 1F8 showing a binding affinity of 8.3 nM with >1000-fold enhancement on inhibition potency compared to the peptide inhibitor. Yeast surface display and fluorescence-activated cell sorting results indicated that 1F8 was highly selective to MMP-14 and competed with TIMP-2 on binding to the catalytic domain of MMP-14. Converting a low-affinity peptide inhibitor into a high potency antibody, the described methods can be used to develop other inhibitory antibodies of therapeutic significance.

SUBMITTER: Nam DH

PROVIDER: S-EPMC6283398 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Generation of inhibitory monoclonal antibodies targeting matrix metalloproteinase-14 by motif grafting and CDR optimization.

Nam Dong Hyun DH Fang Kuili K Rodriguez Carlos C Lopez Tyler T Ge Xin X

Protein engineering, design & selection : PEDS 20161215 2

Matrix metalloproteinase-14 (MMP-14) plays important roles in cancer metastasis, and the failures of broad-spectrum MMP compound inhibitors in clinical trials suggested selectivity is critical. By grafting an MMP-14 specific inhibition motif into complementarity determining region (CDR)-H3 of antibody scaffolds and optimizing other CDRs and the sequences that flank CDR-H3, we isolated a Fab 1F8 showing a binding affinity of 8.3 nM with >1000-fold enhancement on inhibition potency compared to the ...[more]

PMID: 27986919

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