BCR transgenic mice with common leader sequence

A technology of transgenic animals and sequences, which can be used in medical preparations containing active ingredients, anti-animal/human immunoglobulins, and antibody medical components, etc., which can solve problems such as reducing the diversity of polyclonal antibody libraries.

Pending Publication Date: 2022-08-05
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
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AI Technical Summary

Problems solved by technology

Any isolation step that favors some antibodies at the expense of others will further reduce the diversity of the polyclonal antibody repertoire

Method used

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  • BCR transgenic mice with common leader sequence
  • BCR transgenic mice with common leader sequence
  • BCR transgenic mice with common leader sequence

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0127] Selection of the optimal leader peptide coding sequence

[0128] The optimal leader peptide sequences and optimal leader peptide coding sequences for use in the methods, constructs and animals of the present invention are selected as follows. Briefly, an initial set of potential leader peptide sequences was selected based on conservation and consensus of sequences within all leader sequence sets, frequency and usage in human antibody repertoires, and sequence diversity across the initial set was made maximize. Both amino acid and DNA sequences are also ranked based on their ubiquity in human antibody repertoires and in approved antibody drugs, based on the fact that such selection indicates that the sequences are biologically ideal and suitable for commercial antibody producing cells Systems and methods and therapeutic agents for use in humans. The recombinant protein expression efficiency of the set of leader peptides was then evaluated by pairwise evaluation of heav...

Embodiment 2

[0133] Selection of heavy and light chain V gene segments

[0134] V gene segments for use in the methods and mice of the present invention are selected as follows. Briefly, V gene segments for both heavy and light chains are based on their prevalence in human antibody repertoires, in antibody therapeutics that have entered Phase I clinical trials, and in approved antibody drugs. sex to choose. They were also assessed for chemical barriers (such as methionine (especially in CDRs) or presence of unpaired cysteines), as well as sequence barriers like DG and NG, presence of glycosylation sites and immunogenicity Sex - through experimental observations and computational predictions (e.g. by Immunogenicity Assessment Software, EpiVax Inc., Providence, R.I., USA).

[0135] After considering and balancing the above factors, for the heavy chain variable domain locus, the following 19 V gene segments (hIGHV) were selected: 3-23; 5-51; 3-7; 1-2; 1-69- 1;3-48;1-18;1-46;3-21;3-30;3-7...

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Abstract

The invention provides transgenic animals comprising some or all components of human heavy and / or light chain immunoglobulin variable region loci, methods of making such animals, methods of making human antibodies using such animals, and methods of treatment using human antibodies prepared in such animals, wherein the animal comprises in its genome a plurality of human heavy chain V gene segments and / or a plurality of human light chain V gene segments, or both, all of the plurality of human heavy chain V gene segments immediately following a same first leader peptide coding sequence and all of the plurality of human light chain V gene segments immediately following a same second leader peptide coding sequence. The invention also provides a polynucleotide construct comprising two or more human heavy chain or light chain precursor / V gene segments comprising the same leader peptide coding sequence. Such animals, constructs, and methods can be used to efficiently produce an optimal diverse population of antibodies against an antigen of interest, such as a therapeutic antigen of interest.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims priority to US Provisional Application No. 62 / 949,707, filed December 18, 2019, the disclosure of which is incorporated herein by reference. [0003] sequence listing [0004] The electronically filed Sequence Listing is also hereby incorporated by reference in its entirety (file name: 20201120_SEQL_13330WOPCT_GB.txt; creation date: November 20, 2020; file size: 29KB). Background technique [0005] Antibodies are increasingly used as drugs to treat human diseases such as autoimmune diseases and cancer. The earliest such therapeutic antibodies were non-human (eg, mouse) antibodies that elicited a human anti-drug antibody response (eg, a human anti-mouse antibody-HAMA response) and thus could not be administered repeatedly. Subsequent generations of therapeutic antibodies were "chimeric" forms of non-human (usually mouse) antibodies, in which human constant regions replaced non-human constant regio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01K67/027A61K39/00C07K16/18C12N15/10
CPCA01K67/0278A01K2227/105A01K2267/01C07K16/00C07K2317/21C07K2317/56C07K16/18
Inventor R·M·巴恩斯A·拉杰帕尔A·鲁J·M·马杰卡A·弗里德伯格G·吴
Owner BRISTOL MYERS SQUIBB CO
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