IGFBP3 antibodies and therapeutic uses thereof

An antibody and antigen technology, applied in the field of IGFBP3 antibody and its therapeutic application, can solve problems such as not being ideal for antibodies

Pending Publication Date: 2022-07-12
恩瑟拉有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, receptor constructs are less ideal as therapeutics than antibodies

Method used

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  • IGFBP3 antibodies and therapeutic uses thereof
  • IGFBP3 antibodies and therapeutic uses thereof
  • IGFBP3 antibodies and therapeutic uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0290] Example 1: Monoclonal Antibody Development

[0291] Monoclonal anti-IGFBP3 antibodies were discovered using transgenic mice in which the relevant human immunoglobulin sequences have been genetically engineered (Trianni Mouse TM (Trianni)) were introduced into animal genomes.

[0292] Through this technique, chimeric monoclonal antibodies are produced that contain a complete repertoire of human heavy and light chain variable domains and retain mouse constant domains.

[0293] Basically, the Trianni Mouse of the two cohorts TM (Cohort 1: ALD / MDP adjuvant, Cohort 2: SAS / Ribi adjuvant) Immunization with a purified preparation of IGFPP3 antigen (Lot AB08BP1210) was injected twice weekly for 4 weeks, then extended by 2 weeks. Then, antibody-expressing lymphocytes (such as B cells) are recovered from the mice, such cells are fused with myeloid cell lines to prepare immortalized hybridoma cell lines, and such hybridoma cell lines are screened and selected, Hybridoma cell lin...

Embodiment 2

[0336] Inhibition of IGFBP3-TMEM219 binding by hybridoma-produced anti-IGFBP3 mAb

[0337] Novel anti-IGFBP3 monoclonal antibodies produced using hybridomas were screened for their ability to compete with exo-TMEM219 for interaction with IGFBP3 using a competitive ELISA binding assay. IGFBP3, exo-TMEM219 and available antibodies were all used in a 1:1 ratio. Anti-IGFBP3 mAb was able to inhibit IGFBP3-exo-TMEM219 ( figure 1 ). This demonstrates that the anti-IGFBP3 mAbs of the present invention can inhibit the binding of IGFBP3 to the native TMEM219 receptor and may mimic the neutralizing activity of exo-TMEM219 protein.

[0338] A newly generated monoclonal anti-IGFBP3 antibody rescues IGFBP3-damage in a human mini-gut assay

[0339] The newly discovered monoclonal antibody was also tested in a mini-gut test. Briefly, mini-guts were generated from crypts obtained from healthy controls (n=3), cultured in the presence of IGFBP3 for 8 days and treated with exo-TMEM219 or ...

Embodiment 3

[0356] A newly generated monoclonal anti-IGFBP3 antibody rescues IGFBP3-damage in a human mini-gut assay

[0357] Anti-IGFBP3 monoclonal antibodies were tested in the mini-gut assay. Briefly, mini-guts were generated from crypts obtained from healthy controls (n=3), cultured for 8 days after IGFBP3 exposure, and treated with anti-IGFBP3 mAb at a 1:1 ratio (mAb:IGFBP3). The inventors observed that E08 and E20 were comparable to exo-TMEM219 in the self-renewal ability to rescue large crypt organoids in the presence of IGFBP3 among the 8 mAbs, thus supporting protection against IGFBP3-mediated damage on local stem cells. Correlation effect ( Figure 8 ).

[0358] A newly generated monoclonal anti-IGFBP3 antibody rescues IGFBP3-damage on ISC markers

[0359] Anti-IGFBP3 mAb, which was shown to effectively promote mini-gut development, was also able to restore the expression of ISC markers EphB2 and LGR5 ( Figure 9 ). This effect was caspase 8-mediated, as caspase 8 expre...

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Abstract

The present invention relates to antibodies or antigen binding fragments thereof that specifically bind to IGFBP3. The antibody inhibits or reduces the binding of IGFBP3 to the TMEM219 receptor. The invention also relates to a method for the production thereof, pharmaceutical compositions containing said antibodies and uses thereof.

Description

technical field [0001] The present invention relates to an antibody or antigen-binding fragment thereof that specifically binds to human IGFBP3, to a method for its production, a pharmaceutical composition comprising said antibody, and its use. Background technique [0002] IGFBP3 / TMEM219 axis [0003] IGF-binding proteins are a family of seven binding proteins that regulate the bioavailability of insulin-like growth factor (IGF). Among them, IGFBP3 is the most abundant, exists in almost all tissues, and has a high affinity for IGF; in fact, about 80-90% of IGFs bind IGFBP3 and form a ternary complex with the acid labile subunit (ALS) (1). [0004] In addition to being able to regulate IGF availability, IGFBP3 has also been shown to have IGF-independent functions (2). In fact, it is able to associate with cell surface proteins, cell surface receptors with global signal transduction capabilities, intracellular and nuclear proteins (transcription factors), thereby affecting...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/18
CPCC07K16/18C07K2317/24C07K2317/565C07K2317/76C07K2317/92A61P7/00C07K16/22C12N15/66
Inventor G·阿玛贝利P·菲奥里那F·达迪奥
Owner 恩瑟拉有限责任公司
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