Mesothelin antibodies and methods for eliciting potent antitumor activity

摘要

Described herein is the use of phage display antibody engineering technology and synthetic peptide screening to identify SDl and SD2, human single-domain antibodies to mesothelin. SDl recognizes a conformational epitope at the C-terminal end (residues 539-588) of human mesothelin close to the cell surface. SD2 binds full-length mesothelin. To investigate SDl as a potential therapeutic agent, a recombinant human Fc (SDl-hFc) fusion protein was generated. The SDl-hFc protein exhibits strong complement-dependent cytotoxicity (CDC), in addition to antibody- dependent cellular cytotoxicity (ADCC), against mesothelin-expressing tumor cells. Furthermore, the SDl-hFc protein causes significant tumor growth inhibition of tumor xenografts in nude mice. SDl and SD2 are the first human single-domain antibodies targeting mesothelin-expressing tumors.