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Antibodies against CAIX with reduced affinity for neonatal Fc receptor

An affinity, antibody technology, applied in the direction of antibodies, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, preparations for in vivo experiments, etc., can solve problems such as patient exposure

Pending Publication Date: 2022-05-13
泰利克斯国际有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These approaches have achieved varying degrees of success in combating hematopoietic toxicity in small studies but require exposing patients to further medications and treatments and thus remain largely unused

Method used

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  • Antibodies against CAIX with reduced affinity for neonatal Fc receptor
  • Antibodies against CAIX with reduced affinity for neonatal Fc receptor
  • Antibodies against CAIX with reduced affinity for neonatal Fc receptor

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0560] Example 1: Antibodies for Binding to CAIX

[0561] overview

[0562] Humanized antibody variable region genes were cloned into vectors encoding unmodified human IgG1 heavy chain constant domain and human kappa light chain constant domain. The chimeric antibody was additionally cloned into a vector encoding a modified human IgG1 heavy chain constant domain containing mutations H310A and H435Q that abolish FcRn and protein A binding (Andersen et al., 2012), or mutation S228P (to stabilize the hinge (Angal et al., 1993)) and L235E (removing effector function (Reddy et al., 2000)) as well as modified human IgG4 heavy chain constructs of the FcRn ablation mutations described above. Chimeric and humanized antibodies were transiently expressed in HEK EBNA cells and tested for binding to human carbonic anhydrase IX (CAIX) using Biacore single-cycle kinetic analysis. Selected lead antibodies were purified by protein A or protein G and analyzed by analytical SEC, competition ...

example 2

[0601] Example 2: Antibodies for Binding to PSMA

[0602] overview

[0603] The antibody VH gene sequences of two antibodies (ANT4044 and ANT4044-A2) were cloned into three different human IgG double expression vectors encoding unmodified IgG1 containing mutations H310A and H435Q (eliminating FcRn binding and protein A binding ( Andersen et al., 2012)) IgG1 (termed IgG1(H310A, H435Q)), and with the same FcRn depletion mutation as above, as well as the hinge stabilizing S228P mutation (Angal et al., 1993) and the Fc silent L235E mutation (Reddy et al., 2000 ) modified IgG4 (referred to as IgG4 (S228P, L235E, H310A, H435Q)). Each dual expression vector also contained the antibody VK gene sequence common to both ANT4044 and ANT4044-A2.

[0604] A total of five antibodies were transiently transfected and expressed in CHO cells and purified using protein A (ANT4044-A2 IgG1) or protein G (ANT4044 and ANT4044-A2 both expressed as IgG1 (H310A, H435Q) and IgG4 (S228P , L235E, H310...

example 3

[0638] Example 3: Antibody Conjugation

[0639] Antibodies ANT4044-IgG1, ANT4044-A2-IgG1, ANT4044-IgG1 H310A H435Q (also known as ANT4044-IgG1-2M) and ANT4044-IgG4 S228P L235E H310A H435Q (also known as ANT4044-IgG4-4M) with ThioBridge TM - PEG(6u)-DOTA reagent or NHS-DOTA reagent conjugation.

[0640] Thio Bridge TM is a PolyTherics proprietary disulfide-conjugated linker and is described in

[0641] DOTA is the chelator payload, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid monoamide.

[0642] Thio Bridge TM DOTA Conjugation Evaluation: ANT4044-IgG1 was prepared as a 6-10 mg / mL solution in reaction buffer (20 mM sodium phosphate, pH 7.5, 150 mM NaCl, 20 mM ethylenediaminetetraacetic acid (EDTA)). To ANT4044-IgG1 in reaction buffer (6-10 mg / mL, 40°C) was added 6-10 equivalents per antibody of tris(2-carboxyethyl)phosphine (TCEP) or DTT 10 mM. Adjust the antibody concentration to 5 mg / mL by diluting with reaction buffer. The reducing mixture was incubated ...

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Abstract

The present invention relates to anti-CAIX antibodies comprising a heavy chain constant region containing one or more amino acid substitutions as compared to wild-type IgG wherein the one or more amino acid substitutions reduce the affinity of the antibody for neonatal Fc receptor (FcRn) as compared to IgG-based wild-type antibodies, thereby reducing the serum half-life of the modified antibody. The one or more amino acid modifications, which have the effect of reducing FcRn binding, are selected from the group consisting of positions His310, His433, His435, His436, Ile253. The antibodies of the invention are particularly suitable for use in radioimmunotherapy.

Description

technical field [0001] The present invention relates to antibodies, compositions and methods of producing antibodies, particularly specific antibodies conjugated to radioisotopes having reduced serum half-lives for use in radioimmunotherapy. [0002] related application [0003] This application claims priority from Australian Provisional Application AU 2019902343, the entire contents of which are hereby incorporated by reference. Background technique [0004] Radiation therapy is an important form of cancer therapy. Various radiation therapies have been developed to treat tumors. Among them, radioimmunotherapy (RAIT) is an emerging method of delivering radiation therapy. It uses antibodies or antibody fragments to target radioactive isotopes to specific tissues and cells, thereby enhancing the specificity of tumor therapy and reducing toxicity. RAIT further reduces its side effects by using low dose rate radiation. [0005] Radiation damage to healthy tissues and organ...

Claims

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Application Information

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IPC IPC(8): C07K16/30A61K39/395A61K51/10A61P13/12A61P35/00G01N33/534G01N33/574
CPCA61P35/00G01N33/534C07K16/30C07K16/40A61K51/1075G01N33/57438A61K2039/505C07K2317/71C07K2317/94A61K47/6889A61K51/1087A61K2121/00A61K2123/00C07K2317/24C07K16/3069A61K51/1045A61K51/1072G01N33/60C07K2317/732
Inventor M·P·维特克罗夫特C·P·贝伦布鲁赫
Owner 泰利克斯国际有限公司
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