Identification of immunologically protective neo-epitopes for the treatment of cancers

Patent metadata

Field	Value
Publication number	US-12311017-B2
Application number	US-202217725932-A
Country	US
Kind code	B2
Filing date	Apr 21, 2022
Priority date	Sep 10, 2014
Publication date	May 27, 2025
Grant date	May 27, 2025

Abstract

Described herein are methods of identifying immunologically protective neo-epitopes from the cancer tissue DNA of cancer patients using biophysical principles as well as bioinformatics techniques. The identification of immunologically protective neo-epitopes provides pharmaceutical compositions with a limited number of tumor-specific peptides suitable for personalized genomics-driven immunotherapy of human cancer. Specifically disclosed herein is a method of using the conformational stability of an epitope in an MHC protein-binding groove to predict immunogenicity of peptides in a putative neo-peptide set from a tumor from a cancer patient. Pharmaceutical compositions and methods of administration are also included.

First claim

The invention claimed is:

1. A method of treating a cancer patient, the method comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and
(i) one or more immunologically protective neo-epitope peptides,
(ii) one or more polypeptides containing immunologically protective neo-epitopes, or
(iii) one or more polynucleotides encoding the one or more immunologically protective neo-epitopes,
wherein
a conformational stability of each of the immunologically protective neo-epitope bound to a major histocompatibility complex class I (MHC I) protein or a major histocompatibility complex class II (MHC II) protein, as determined by molecular modeling or by experiment, is higher than a corresponding wild-type epitope,
each of the immunologically protective neo-epitopes have a measured IC50 for H-2Kd or human leukocyte antigen (HLA) of greater than 100 nM, and
each of the immunologically protective neo-epitopes is specific to a tumor from a cancer patient and does not include epitopes from known cancer-causing pathways.

2. The method of claim 1 , wherein the conformational stability is determined for the entire immunologically protective neo-epitopes.

3. The method of claim 1 , wherein each of the immunologically protective neo-epitopes have a measured IC50 for H-2K d or human leukocyte antigen (HLA) of greater than 500 nM.

4. The method of claim 1 , wherein the MHC protein is an MHC I protein and the immune response is a CD8+ response.

5. The method of claim 1 , wherein the pharmaceutical composition comprises 1 to 100 immunologically protective neo-epitope peptides or polynucleotides.

6. The method of claim 1 , further comprising an adjuvant, an immune-modulating agent, or a combination of the foregoing.

7. The method of claim 6 , wherein the immune-modulating agent is a TLR ligand or an antibody.

8. The method of claim 1 , wherein the cancer patient is suffering from a solid or liquid cancer.

9. The method of claim 1 , further comprising treating the cancer patient with radiation therapy, chemotherapy, surgery, or a combination thereof.

10. The method of claim 1 , wherein the conformation stability is measured by root mean squared fluctuations (RMSF).

11. The method of claim 1 , wherein at least a portion of the α-carbons of each immunologically protective neo-epitope bound to the MHC I protein or the MHC II protein has a root mean squared fluctuations (RMSF) of less than 2 Å.

12. The method of claim 1 , wherein at least a portion of the α-carbons of each immunologically protective neo-epitope bound to the MHC I protein or the MHC II protein has a root mean squared fluctuations (RMSF) of less than 1.5 Å.

13. The method of claim 1 , wherein at least a portion of the α-carbons of each immunologically protective neo-epitope bound to the MHC I protein or the MHC II protein has a root mean squared fluctuations (RMSF) of less than 1.2 Å.

14. The method of claim 1 , wherein at least a portion of the α-carbons of each immunologically protective neo-epitope bound to the MHC I protein or the MHC II protein has a root mean squared fluctuations (RMSF) of less than 0.9 Å.

15. The method of claim 1 , wherein the conformational stability is determined for the C-terminal portion of the immunologically protective neo-epitopes.

16. The method of claim 1 , wherein the conformational stability is determined for the central portion of the immunologically protective neo-epitopes.

17. The method of claim 1 , wherein the conformational stability is determined for the N-terminal portion of the immunologically protective neo-epitopes.

18. The method of claim 1 , wherein the MHC protein is an MHC II protein, and the immune response is a CD4+ response.

Assignees

• Univ Connecticut
• Univ Notre Dame Du Lac

Inventors

• Srivastava Pramod K
• Baker Brian M

Classifications

• C12Q1/6869

  Methods for sequencing · CPC title

• A61K39/395

  Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• A61K39/0011 Primary

  Cancer antigens · CPC title

• A61P35/00

  Antineoplastic agents · CPC title