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Antibodies that target HIV gp120 and methods of use

A HIV-1 and antibody technology, applied in chemical instruments and methods, antibodies, antibody medical components, etc., can solve the problems of virus coverage, pharmacokinetics, multi-specificity and other characteristic limitations of antibody therapy

Pending Publication Date: 2021-02-12
GILEAD SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therapeutic use of antibodies can be limited by their viral coverage in patients, pharmacokinetics, multispecificity, and other properties

Method used

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  • Antibodies that target HIV gp120 and methods of use
  • Antibodies that target HIV gp120 and methods of use
  • Antibodies that target HIV gp120 and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0415] Example 1: ADCC Activity of Antibody A

[0416] Use of HIV-infected CEM.NKr.CCR5 + Luc + cells and primary human NK effector cells from independent healthy donors were assayed in vitro for antibodies against the HIV-infected target CD4 + ADCC of T cells.

[0417] The studies included both PGT121-sensitive and PGT121-resistant viruses as well as antibodies with modifications to the Fc of Antibody A (Fc modifications). Table 1 summarizes the presence of 5 mg / mL human serum IgG and using primary human NK cells from three independent human donors and CEM.NKr.CCR5 infected with virus isolates 92US712 or 92US657 + Luc + Lethality and potency of antibodies A, A-1, A-2, A-3, A-4, A-5 and A-6 when assayed in cells.

[0418] Table 1. ADCC activity

[0419]

[0420] For a dose response of Emax 50 Annotated as >100 μg / mL.

[0421] The Fc-modified antibody showed increased killing of HIV-1-infected target CD4 T cells compared to antibody A in vitro by primary human NK c...

Embodiment 2

[0448] Example 2: Antibody Campaign (Campaign)

[0449] Comparison of the sequences of Antibody A and Antibody B to the human germline revealed several mutations, insertions and deletions, both internal and external to the CDRs. Briefly, a continuum of germline mismatches in the heavy chain framework region 3 (HCFR3) was identified at positions 72-78 of the heavy chain (HC). Four amino acid insertions were identified between positions 74 and 75 of HC FR3. A germline deletion was identified in CDR L1 at positions 27-30 of the light chain (LC). A continuum of germline mismatches was identified at positions 65-77 in the light chain framework region 3 (LC FR3). An N72-linked consensus glycosylation motif was identified at positions 72–74 in LC FR3. A germline deletion in CDR L3 was identified at positions 92-95. Two residues (F98 and G99) that are highly conserved in human IgG light chains were mutated in both Antibody A and Antibody B.

[0450]Mass spectrometry studies wer...

Embodiment 3

[0471] Embodiment 3: mass spectrometry

[0472] Antibody A-1 was transiently expressed in ExpiCHO cells and protein A purified using standard methods. Samples were denatured and reduced by using 4M guanidine hydrochloride and 50 mM DTT (final concentration) and heating at 60°C for 20 minutes. Samples were desalted on-line while the reduced heavy and light chains were separated on a BEH C4 reversed-phase column (before injection into the source of a Waters Synapt G2Si hybrid time-of-flight mass spectrometer). Packets of multiply charged protein peaks were deconvoluted using the maximum entropy deconvolution algorithm. The results show that the Antibody A light chain is glycosylated. The observed light chain mass spectra revealed the presence of G0-glycan modifications and other glycan-related mass heterogeneity. This observation is consistent with the presence of a consensus glycosylation motif at N72 in the antibody AVL domain (NLT) and a previous crystal structure of ant...

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Abstract

Antibodies that bind to HIV gp120 and neutralize HIV are disclosed. Also disclosed are methods of using such antibodies alone or in combination with other therapeutic agents to treat or prevent HIV infection.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 62 / 693,642, filed July 3, 2018, and U.S. Provisional Patent Application No. 62 / 810,191, filed February 25, 2019, the entire contents of which are adopted Incorporated by reference herein for all purposes. [0003] sequence listing [0004] This application contains a Sequence Listing, which has been filed electronically in ASCII format, the entire contents of which are hereby incorporated by reference. Said ASCII copy, created on June 10, 2019, is named 1232_P2F_SL.txt and is 899,216 bytes in size. technical field [0005] The present disclosure relates to antibodies and antigen-binding fragments thereof for use in the treatment and / or prevention of human immunodeficiency virus (HIV) infection. Background technique [0006] Human immunodeficiency virus (HIV) infection and related diseases are major public health proble...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P31/18C07K16/10
CPCC07K16/1063C07K14/7051C12N5/0636A61K39/42A61K31/4745A61K45/06A61P31/18C07K2317/21C07K2317/31C07K2317/33C07K2317/34C07K2317/41C07K2317/52C07K2317/54C07K2317/55C07K2317/565C07K2317/567C07K2317/622C07K2317/71C07K2317/72C07K2317/73C07K2317/732C07K2317/76C07K2317/92C07K2317/94C07K2319/00C12N2510/00A61K2039/505A61K2300/00A61K2039/545
Inventor M·巴拉克利什南B·A·卡尔M·S·亨M·坎瓦尔C·S·佩斯D·雷德尔M·R·谢瑙尔L·塞拉菲尼H·T·斯蒂芬森N·D·汤姆森H·于张学
Owner GILEAD SCI INC
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