Mesothelin antibodies and methods for eliciting potent antitumor activity

Abstract

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.

Description

[0001] Cross reference to related applications

[0002] This application claims the benefit of US Provisional Application No. 61 / 706,396, filed September 27, 2012, the contents of which are hereby incorporated in their entirety. technical field

[0003] The present disclosure relates to monoclonal antibodies, such as monoclonal antibodies specific for a single domain of mesothelin. The disclosure further relates to the use of such antibodies, such as in the diagnosis and treatment of cancer. Background technique

[0004] Since mesothelin is highly expressed in malignant mesothelioma (Chang et al., Cancer Res 52:181-186, 1992; Chang and Pastan, proc Natl Acad Sci USA 93:136-140, 1996) and in other solid tumors, such as Highly expressed in gastric cancer, squamous cell carcinoma, prostate cancer, pancreatic cancer, lung cancer, cholangiocarcinoma, breast cancer and ovarian cancer, so mesothelin is considered as a therapeutic target. (Hassan et al., Clin. Cancer Res. 10: 3937...

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