Antibodies for binding to PSMA with reduced affinity for neonatal Fc receptor

A kind of affinity and antibody technology, applied in the direction of non-active ingredient medical preparations, antibodies, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, etc., can solve problems such as patient exposure

Pending Publication Date: 2022-05-27
泰利斯制药(创新)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 for binding to PSMA with reduced affinity for neonatal Fc receptor
  • Antibodies for binding to PSMA with reduced affinity for neonatal Fc receptor
  • Antibodies for binding to PSMA with reduced affinity for neonatal Fc receptor

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0432] Example 1: Antibodies for binding to PSMA

[0433] Overview

[0434] The antibody VH gene sequences of two antibodies (ANT4044 and ANT4044-A2) were cloned into three different human IgG dual expression vectors encoding unmodified IgG1, containing the mutations H310A and H435Q (abolishing FcRn binding and protein A binding ( Andersen et al., 2012)) IgG1 (referred to as IgG1 (H310A, H435Q)), and with the same FcRn elimination mutations described above, as well as the hinge-stabilizing S228P mutation (Angal et al., 1993) and the Fc-silencing L235E mutation (Reddy et al., 2000 ) modified IgG4 (referred to as IgG4 (S228P, L235E, H310A, H435Q)). Each dual expression vector also contains antibody Vκ gene sequences common to both ANT4044 and ANT4044-A2.

[0435] 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 (...

example 2

[0469] Example 2: Antibody Conjugation

[0470] Antibodies ANT4044-IgG1, ANT4044-A2-IgG1, ANT4044-IgG1 H310A H435Q (aka ANT4044-IgG1-2M) and ANT4044-IgG4 S228P L235E H310A H435Q (aka ANT4044-IgG4-4M) with ThioBridge TM -PEG(6u)-DOTA reagent or NHS-DOTA reagent conjugation.

[0471] ThioBridge TM is a PolyTherics proprietary disulfide conjugated linker and is described in

[0472] DOTA is the chelator payload, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid monoamide.

[0473] ThioBridge TM DOTA Conjugation Assessment: 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 of tris(2-carboxyethyl)phosphine (TCEP) or DTT 10 mM per antibody. The antibody concentration was adjusted to 5 mg / mL by dilution with reaction buffer. The reduction mixture was incubated at 37°C-40°C fo...

example 3

[0475] Example 3: Pharmacokinetic Analysis of Antibodies for Binding PSMA

[0476] The serum half-life of the following antibodies was assessed using a method similar to that described in Example 1: J591 IgG lysine DOTA conjugate (for binding PSMA control antibody), ANT4044 lysine DOTA conjugate (ANT4044-K-DOTA), ANT4044-A2 lysine DOTA conjugate (ANT4044-A2-K-DOTA), ANT4044 with amino acid substitutions in the FcRn binding region , a lysine DOTA conjugate (ANT4044-FcRn-K-DOTA) and ANT4044, a lysine DOTA conjugate (ANT4044-FcRg-K-DOTA) with amino acid substitutions in the FcRn and Fcγ receptor binding regions. The results are shown in figure 1 middle.

[0477] figure 2 The mean area under the curve (AUC, top) and clearance (CL, bottom) for each antibody tested are shown. Error bars represent standard deviation of the mean.

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Abstract

The present invention relates to anti-PSMA 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 an IgG-based wild-type antibody, 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 with reduced serum half-life for use in radioimmunotherapy. [0002] Related applications [0003] This application claims priority from Australian Provisional Application AU 2019902344, the entire contents of which are hereby incorporated by reference. Background technique [0004] Radiation therapy is an important form of tumor 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 direct radioisotopes to specific tissues and cells, thereby enhancing the specificity of tumor treatments and reducing toxicity. RAIT further reduces its side effects by using low dose rate radiation. [0005] Radiation damage to healthy tissues and organs is a ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/30G01N33/534G01N33/574A61K39/395A61K51/10A61P13/08A61P35/00
CPCA61P35/00C07K16/3069G01N33/534A61K51/1075A61K2039/505C07K2317/71C07K2317/94A61K51/1087A61K47/6889A61K2121/00A61K2123/00C07K2317/52C07K2317/53C07K2317/524C07K2317/528C07K2317/24A61K51/1072A61K51/1093G01N33/60
Inventor M·P·维特克罗夫特C·P·贝伦布鲁赫
Owner 泰利斯制药(创新)有限公司
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