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Compositions and methods for immunotherapy

a technology of immunotherapy and compositions, applied in the field of immunotherapy compositions and methods, can solve the problems of significant limitations of dc immunotherapy, as many immunotherapies do, and achieve the effect of improving the immunotherapy

Inactive Publication Date: 2018-08-02
NEXIMMUNE INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a method for inducing antigen-specific T cells using a molecular complex that contains a co-stimulatory molecule and antigen-presenting molecules. The complex includes a fusion of an HLA amino acid sequence with immunoglobulin sequences to create a more stable and effective binding to the T cells. The complex can be presented on beads or particles to enhance the stability and binding affinity of the antigen to T cells. This technology has applications in immunotherapy and research on immune responses.

Problems solved by technology

However, DC immunotherapy, like many immunotherapies faces significant limitations.

Method used

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  • Compositions and methods for immunotherapy
  • Compositions and methods for immunotherapy
  • Compositions and methods for immunotherapy

Examples

Experimental program
Comparison scheme
Effect test

example 1

Germline Humanized Variable Regions and Human Constant Region Sequences

[0101]This Example demonstrates, inter alia, a design of sequences for germline humanized (CDR grafted) antibodies from a mouse anti-CD28 antibody template; a design of human constant region sequences including human IgG4 containing the S241P (Kabat numbering) hinge stabilizing mutation, the L248E (Kabat numbering) mutation to remove residual Fe gamma receptor binding and a Cys residue (S473C, Kabat numbering) suitable for coupling the antibody; a design of a variant germline humanized antibody V domain with potential non-binding to CD28; a design of a linker sequence for the fusion of HLA-A*02:01 to the N-terminus of the germline humanized antibodies that does not contain potential T cell epitopes.

[0102]The starting anti-CD28 antibody was the murine 9.3 monoclonal antibody (Tan et al., J. Exp. Med. 1993 177:165). Structural models of the 9.3 antibody V regions were produced using Swiss PDB and analyzed in order ...

example 2

Linkers for Fusion of HLA-A*02:01 to Humanized Antibodies

[0112]Linkers for the fusion of HLA-A*02:01 (IMGT Accession No. HLA00005) to the N-terminus of humanized anti-CD28 antibodies were constructed and incorporated analysis by iTope™ and TCED™ to remove potential immunogenicity.

[0113]The iTope™ software predicts favorable interactions between amino acid side chains of a peptide and specific binding pockets (in particular pocket positions; p1, p4, p6, p7 and p9) within the open-ended binding grooves of 34 human MHC class II alleles. These alleles represent the most common HLA-DR alleles found world-wide with no weighting attributed to those found most prevalently in any particular ethnic population. Twenty of the alleles contain the ‘open’ p1 configuration and fourteen contain the ‘closed’ configuration where glycine at position 83 is replaced by a valine. The location of key binding residues is achieved by the in silico generation of 9mer peptides that overlap by one amino acid sp...

example 3

imization of Sequences and Expression Cloning

[0119]Codons were optimized using GeneOptimizer®, and optimized sequences were cloned for expression as shown below.

[0120]Sequences were engineered with PmeI restriction sites, Kozak sequence, and signal peptide for expression in NS0 cells. Translation starts immediately downstream of the Kozak sequence.

[0121]The full translated amino acid sequence of the HLA-IgG4HC fusion is shown in FIG. 10.

[0122]The translated sequence of LC3 (VK3) is shown in FIG. 11.

[0123]The translated sequence for HC1 is shown in FIG. 12.

[0124]The translated sequence for HC2 is shown in FIG. 13.

[0125]Human 32 microglobulin was also expressed.

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Abstract

The present invention provides compositions and methods for immunotherapy, which include shelf-stable pharmaceutical compositions for inducing antigen-specific T cells. Such compositions are employed as components of an artificial antigen presenting cell (aAPC), to provide a patient with complexes for presentation of an antigen (e.g., a tumor antigen) and / or a T cell co-stimulatory molecule.

Description

PRIORITY[0001]This Application claims the benefit of, and priority to, U.S. Provisional Application No. 61 / 838,547, filed Jun. 24, 2013, and U.S. Provisional Application No. 61 / 948,916, filed Mar. 6, 2014, which are hereby incorporated by reference in their entireties.FIELD OF THE INVENTION[0002]The present invention relates to compositions, including pharmaceutical compositions, and methods that are useful for immunotherapy.BACKGROUND[0003]An antigen-presenting cell (APC) is a cell that processes and displays antigenic peptides in complexes with major histocompatibility complex (MHC) proteins on their surfaces. Effector cells, such as T-cells, may recognize these peptide-MHC (pMHC) complexes using receptors, such as T-cell receptors (TCRs).[0004]Dendritic cells (DCs) are an example of an antigen presenting cell that can be stimulated to effectively present antigen and support expansion of immune effect cells, thereby activating a cytotoxic response towards an antigen. In some immun...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K47/60C12N9/02A61K38/17A61K39/00A61K39/39A61K39/395A61K39/44C07K14/74C07K16/28C07K16/46A61K47/69
CPCA61K47/6937C07K2317/20C07K2317/52C07K2317/565C07K2317/94C07K2319/30C12Y114/18001A61K38/1774A61K39/44C07K14/70539C07K16/465A61K2039/605A61K39/39C07K2317/75C07K2317/24A61K2039/505C07K16/2818A61K2039/6093A61K39/0011A61K39/3955C12N9/0071A61K47/60A61P35/00A61P37/02A61K2039/55555A61K39/001191A61K39/001186A61K39/001156A61K39/001192A61K39/001184A61K39/001188A61K39/395
Inventor MCCREEDY, BRUCEJONES, TIMOTHY DAVIDCARR, FRANCIS JOSEPH
Owner NEXIMMUNE INC
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