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Anti-CD45 antibodies and conjugates thereof

A technology of antibodies and antigens, applied in the direction of antibodies, anti-animal/human immunoglobulins, drug combinations, etc., can solve problems such as difficulty in ensuring HSC transplantation, hindering, and hindering implantation of exogenous HSC grafts

Pending Publication Date: 2022-08-02
美真达治疗公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite the significant therapeutic potential of hematopoietic stem cells (HSCs), the limiting factor hindering their clinical application is the difficulty in ensuring engraftment of HSC grafts in the host
Specifically, hematopoietic stem cell therapy involving antibodies targeting cell surface antigens on endogenous HSCs can trigger unwanted immune stimulatory and effector functions, thereby hampering engraftment of exogenous HSC grafts

Method used

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  • Anti-CD45 antibodies and conjugates thereof
  • Anti-CD45 antibodies and conjugates thereof
  • Anti-CD45 antibodies and conjugates thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[1049] Example 1. Identification of anti-CD45 antibodies Abl-Ab7

[1050] A fully human library was screened and anti-human CD45 antibodies Ab1, Ab2, Ab3, Ab4, Ab5, Ab6 and Ab7 were identified. Each of the aforementioned antibodies is capable of internalization on CD45 expressing cells. The following examples provide additional details regarding library screening and the resulting antibodies.

[1051] Yeast display

[1052] Yeast display libraries displaying fully human antibodies (natural or synthetic) were screened for binding to the extracellular domain of human CD45 (isoform CD45RABC; Uniprot: P08575-3) and non-human primate (NHP) CD45. Yeast cells are selected that encode antibodies that bind to the recombinant CD45 antigen. Nucleic acid sequences representing antibodies from selected yeast cells are isolated according to techniques known in the art.

[1053] Specifically, screening was performed to identify human and NHP cross-reactive anti-CD45 antibodies. The firs...

example 2

[1059] Example 2. In vitro stability analysis of anti-CD45 antibodies

[1060] The stability of the antibodies identified in Example 1 was evaluated under various stress conditions. These studies identify VH / VL framework and CDR amino acids that can readily form post-translational modifications that can affect antibody heterogeneity and / or binding.

[1061]A two-week stability assay was performed by incubating Ab3 and Ab4 at 4°C, 25°C and 40°C for 15 days and then analyzing the antibodies by hydrophilic interaction chromatography (HIC). Briefly, 25 micrograms of the indicated antibodies were injected onto a Tosoh TSKgel Phenyl-5PW 7.5 mm ID x 7.5 cm 10 micron column (Cat. No. 07573) on a Waters ARCHPLC / UPLC system. The HIC elution profile of the antibody exhibits a relatively hydrophilic front peak with increasing thermal stress. This hydrophilic pre-peak indicates a potential post-translational modification (eg oxidation or deamidation) site. Peptide mapping was then perfo...

example 3

[1063] Example 3. In vitro binding assay of anti-CD45 antibodies

[1064] The antibodies described in Examples 1 and 2 were studied to determine their binding characteristics to human CD45 and to assess their ability to cross-react with rhesus and cynomolgus CD45.

[1065] Antibody binding studies were performed using Biolayer Interferometry (BLI) using Pall ForteBio OctetRed96 in 1×PBS supplemented with 0.1% w / v bovine serum albumin at 25°C. Each purified human antibody was immobilized on an anti-human Fc biosensor (AHQ; Pall ForteBio 18-5001) and mixed with 50 nM of purified human, rhesus or cynomolgus CD45 extracellular domain (purified for affinity maturation). Lines Ab2-Ab7) were grown with 100 nM human CD45 and 300 nM rhesus or cynomolgus CD45 (for the parental clone Ab1).

[1066] Apparent monovalency was determined by partial complete fitting of each IgG to the purified human, cynomolgus or rhesus CD45 extracellular domain using a 1:1 binding model as calculated by Fo...

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Abstract

Disclosed herein are anti-CD45 antibodies, antigen-binding fragments thereof, and antibody drug conjugates (ADCs) that specifically bind to human CD45. The antibodies and ADCs can be used in therapeutic methods including methods of depleting CD45 + cells in a patient. The compositions and methods described herein can be used for direct treatment of conditions, for example, by depleting CD45 + cancer cells or populations of autoimmune cells. The compositions and methods described herein can also be used to prepare a patient for hematopoietic stem cell transplantation therapy and to improve the implantation of hematopoietic stem cell grafts by selectively depleting endogenous CD45 + cells prior to the transplantation procedure.

Description

[0001] related applications [0002] This application claims US Provisional Application No. 62 / 929,137, filed on November 1, 2019; US Provisional Application No. 62 / 929,194, filed on November 1, 2019; filed on November 1, 2019 US Provisional Application No. 62 / 929,207, filed on November 1, 2019; US Provisional Application No. 62 / 929,288, filed November 1, 2019; US Provisional Application No. 62, filed November 1, 2019 / 929,601; US ​​Provisional Application No. 62 / 929,283, filed November 1, 2019; US Provisional Application No. 62 / 929,347, filed November 1, 2019; US Provisional Application No. 62 / 940,742, filed on February 18, 2020; US Provisional Application No. 62 / 978,147, filed February 18, 2020; US Provisional Application No. 63, filed April 24, 2020 / 015,348; U.S. Provisional Application No. 63 / 046,046, filed June 30, 2020; U.S. Provisional Application No. 63 / 046,164, filed June 30, 2020; and Priority to U.S. Provisional Application No. 63 / 084,903, filed on the 29th. The e...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28A61K39/395A61P35/00
CPCC07K16/289C07K2317/21C07K2317/94C07K2317/92C07K2317/33C07K2317/34C07K2317/77A61P35/00C07K2317/24A61K47/6831A61K47/6849A61K47/68035A61K47/6803A61K2039/505A61P37/06A61P35/02A61K35/28A61K2035/124C07K2317/52C07K2317/565C07K2317/73
Inventor A.博伊塔诺M.库克C.麦克多纳R.帕尔乔杜里R.潘沃B.R.佩尔斯P.F.维德布姆P.A.克鲁伊特
Owner 美真达治疗公司
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