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Methods of treating immunotherapy-related toxicity using a gm-csf antagonist

A GM-CSF, immunotherapy technology, used in the use of GM-CSF antagonists to treat immunotherapy-related toxicity, can solve problems such as unknown long-term effects and prolonged hospitalization

Pending Publication Date: 2021-07-23
赫曼尼根公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These toxicities are associated with prolonged hospitalization, intensive care unit (ICU) stay, and the long-term effects of NT are unknown

Method used

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  • Methods of treating immunotherapy-related toxicity using a gm-csf antagonist
  • Methods of treating immunotherapy-related toxicity using a gm-csf antagonist
  • Methods of treating immunotherapy-related toxicity using a gm-csf antagonist

Examples

Experimental program
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preparation example Construction

[0304] Preparation of IV.hGM-CSF Antibody

[0305] Antibodies of the present invention may include such as figure 1 V shown in H Any one of areas VH#1, VH#2, VH#3, VH#4, or VH#5. In some embodiments, antibodies of the invention may include figure 1 V shown in L Any one of areas VK#1, VK#2, VK#3 or VK#4. In some embodiments, the antibody has figure 1 V shown in H zone VH#1, VH#2, VH#3, VH#4 or VH#5; and if figure 1 V shown in L Region VK#1, VK#2, VK#3 or VK#4, as described, for example, in US Patent Nos. 8,168,183 and 9,017,674, each of which is incorporated herein by reference in its entirety.

[0306] Antibodies can be tested to confirm that the antibodies retain activity to antagonize hGM-CSF activity. Antagonist activity can be determined using any number of endpoints, including proliferation assays. Neutralizing antibodies and other hGM-CSF antagonists can be identified or evaluated using a number of assays that assess hGM-CSF function. For example, cell-based h...

example 1

[0357] Example 1 - Exemplary Humanized Antibodies to GM-CSF

[0358] A panel of engineered Fab' molecules with cl9 / 2 specificity was generated from an epitope-focused human V segment library as described in US Patent Application Publication Nos. 20060134098 and 20050255552. The epitope-focused library was constructed from human V segment library sequences joined to the CDR3-FR4 region containing the BSD sequence in CDRH3 and CDRL3 and the human germline J segment sequence. For the heavy chain a human germline JH4 sequence was used and for the light chain a human germline JK4 sequence was used.

[0359] Full-length human engineered V regions that support binding to recombinant human GM-CSF were selected from a Vhl-restricted library. As described in US Patent Application Publication No. 20060134098, a "full-length" V-κ library was used as the basis for constructing a "cassette" library in which only part of the murine cl9 / 2 V segment was initially replaced by a library of huma...

example 2

[0366] Example 2—Evaluation of Human Engineered GM-CSF Antibodies

[0367] This example was evaluated in a cell-based assay compared to a chimeric IgGlk antibody (Ab2) with variable regions from mouse antibody LMM102 (Nice et al., Growth Factors 3:159, 1990) The binding activity and biological efficacy of the human engineered anti-GM-CSF antibody were investigated. Ab1 is a human engineered IgG1k antibody against GM-CSF with the same constant region as Ab2.

[0368] Surface Plasmon Resonance Analysis of Binding of Human GM-CSF to Ab1 and Ab2

[0369] Surface plasmon resonance analysis was used to compare the binding kinetics and monovalent affinities of the interaction of Ab1 and Ab2 with glycosylated human GM-CSF using a Biacore 3000 instrument. Ab1 or Ab2 was captured onto the Biacore chip surface using polyclonal anti-human F(ab')2. Glycosylated recombinant human GM-CSF expressed from human 293 cells was used as analyte. Kinetic constants were determined in 2 independen...

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Abstract

Methods for neutralizing and / or removing human GM-CSF in a subject in need thereof, comprising administering to the subject CAR-T cells having a GM-CSF gene knockout (GM-CSFk / o CAR-T cells) are provided. Also provided are methods for GM-CSF gene inactivation or GM-CSF knockout (KO) in a cell comprising targeted genome editing or GM-CSF gene silencing. Methods for preventing / treating immunotherapy-related toxicity, comprising administering to the subject CAR-T cells having a GM-CSF gene inactivation or GM-CSF knockout (GM-CSFk / o CAR-T cells), wherein the GM-CSF gene is inactivated or knocked out and / or a recombinant GM-CSF antagonist are provided. Methods for reducing a level of a cytokine or chemokine other than GM-CSF in a subject having immunotherapy-related toxicity comprising administering to the subject a recombinant hGM-CSF antagonist are provided. Also provided are methods for treating or preventing immunotherapy-related toxicity in a subject, comprising administering to the subject chimeric antigen receptor-expressing T-cells (CAR-T cells), the CAR-T cells having a GM-CSF gene knockout (GM-CSFk / o CAR-T cells). Methods for preventing or reducing blood-brain barrier disruption in a subject treated with immunotherapy, the method comprising administering CAR-T cells having a GM-CSF gene knockout (GM-CSFk / o CAR-T cells) to the subject, also are provided.

Description

[0001] Cross References to Related Applications [0002] This application is a continuation-in-part of U.S. Application No. 16 / 283,694, filed February 22, 2019, which is a continuation-in-part of U.S. Application No. 16 / 248,762, filed January 15, 2019. Said U.S. application is a continuation-in-part of U.S. Application No. 16 / 204,220, filed November 29, 2018, which is a continuation-in-part of U.S. Application No. 16 / 149,346, filed October 2, 2018 , said U.S. application claims priority to U.S. Provisional Application Nos. 62 / 567,187, filed October 2, 2017, and 62 / 729,043, filed September 10, 2018, and the present application claims priority in 2018 priority to PCT Application No. PCT / US2018 / 053933, filed October 2, 2018, which is hereby incorporated by reference herein. technical field [0003] The present invention relates to a method for neutralizing and / or removing human GM-CSF from a subject in need thereof, said method comprising administering to said subject CAR-T cell...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K35/17A61K39/395A61K39/44A61P35/02C07K16/24C07K16/28C12N5/0783
CPCA61K38/193A61P35/02A61K2039/55516C07K16/243C07K2317/55C07K2317/24C07K2317/92A61K2039/505A61K2239/48A61K39/464429A61K39/464406A61K2239/38A61K39/4631A61K39/4611A61K39/464412A61K2239/31A61K31/7088C07K16/2866A61K35/17A61K39/001112A61K48/005A61K2239/46
Inventor 卡梅龙·达兰特达勒·沙佩尔
Owner 赫曼尼根公司
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