Mesothelin antibodies and methods for eliciting potent antitumor activity

A mesothelin and antibody technology, applied in the direction of anti-tumor drugs, chemical instruments and methods, antibodies, etc., can solve problems such as obstacles and lack of targeted mesothelin therapy

Active Publication Date: 2015-09-30
UNITED STATES OF AMERICA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although many known mesothelin monoclonal antibodies are available, none exhibit complement-dependent cytotoxicity (CDC) against tumor cells
Therefore, current mesothelin-targeted therapies are hampered by the lack of anti-mesothelin monoclonal antibodies with potent CDC

Method used

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  • Mesothelin antibodies and methods for eliciting potent antitumor activity
  • Mesothelin antibodies and methods for eliciting potent antitumor activity
  • Mesothelin antibodies and methods for eliciting potent antitumor activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0270] Example 1: Materials and methods

[0271] This example describes the experimental procedure used for the studies described in Example 2.

[0272] cell culture

[0273] Human cholangiocarcinoma (CCA) cell line (KMBC, Mz-ChA- 1 and HuCCT-1), and A431 (epidermal carcinoma), NCI-H226 (mesothelioma), EKVX (human non-small cell lung cancer or NSCLC), OVCAR-8 (ovarian carcinoma), and L55 (NSCLC) cell growth. A431 / H9 is a transfected A431 cell line that stably expresses human mesothelin (Ho et al., Clin Cancer Res 11:3814-3820, 2005). Make HEK-293F cell line (Invitrogen, Carlsbad, CA) in FreeStyle TM Grow in serum-free medium (Invitrogen). All cell lines were allowed only a few passages (less than 1 month) after the primary freeze was thawed to reduce the total passage number to less than 15, where the primary freeze occurred immediately after the cell lines were obtained. All cell lines can be detected and identified based on morphology and growth rate, and are mycoplasma...

Embodiment 2

[0293] Example 2: Human single domain antibodies elicit potent antitumor activity by targeting epitopes in mesothelin near the surface of cancer cells

[0294] This example describes the identification and characterization of a human single domain antibody specific for a C-terminal epitope of human mesothelin.

[0295] Discovery and preparation of SD1 human antibody

[0296] To search for new anti-mesothelin monoclonal antibodies targeting sites close to the cell surface, a C-terminal mesothelin peptide was designed to screen small-size binder (VH) libraries. The human mesothelin (MSLN) gene encodes a precursor protein containing 622 amino acids (GenBank accession number: AY743922). When transported into the endoplasmic reticulum, the N-terminal signal peptide (residues: 1-33) and the C-terminal GPI anchor additional (addition) signal peptide (predicted cleavage site: Ser598) are removed, after The latter are replaced by GPI anchors. Using big-PI prediction software, the GP...

Embodiment 3

[0324] Example 3: Use of Mesothelin-Specific Monoclonal Antibodies for Detecting Cancer in a Subject or Determining a Cancer Diagnosis in a Subject

[0325] This example describes the detection of cancer in a subject using a mesothelin-specific monoclonal antibody (e.g., SD1 or SD2, or a monoclonal antibody comprising the CDR sequences of SD1 or SD2), such as the monoclonal antibodies disclosed herein . This example further describes the use of these antibodies to determine a cancer diagnosis in a subject.

[0326] Blood samples from those diagnosed or suspected to have a mesothelin-positive cancer (i.e., a cancer that overexpresses mesothelin, such as mesothelioma, prostate cancer, lung cancer, gastric cancer, squamous cell carcinoma, pancreatic cancer, cholangiocarcinoma, triple-negative patients with breast or ovarian cancer). Blood samples obtained from patients without cancer can be used as controls. An ELISA test is performed to detect the presence of soluble mesothel...

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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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/30A61K39/395A61P35/00
CPCG01N2333/705C07K2317/21C07K2319/00C07K16/30C07K2317/732C07K2317/734G01N33/57492C07K2317/569C07K2317/73C07K2317/56C07K2317/30A61K2039/505C07K2317/52A61P35/00A61P35/04
Inventor 何苗壮I·H·帕斯坦D·S·迪米特洛夫唐喆伟丰明乾高威
Owner UNITED STATES OF AMERICA
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