IP Library › Granted Patent US 12,311,017
Granted Patent B2
US 12,311,017 · App. 17/725,932 · Granted May 27, 2025

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

Inventors: Pramod K. Srivastava (Avon, CT); Brian M. Baker (Granger, IN)
Assignees: UNIVERSITY OF CONNECTICUT; UNIVERSITY OF NOTRE DAME DU LAC
A61K39/0011A61K39/395C12Q1/6869C07K2317/92
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Quick Facts
Patent No.
US 12,311,017
App. No.
17/725,932
Granted
May 27, 2025
Kind
B2
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.

Claims (25)

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.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 18, 2022
From: SRIVASTAVA, PRAMOD K.
To: UNIVERSITY OF CONNECTICUT
Reel/Frame 060840/0248 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 17, 2022
From: BAKER, BRIAN M.
To: UNIVERSITY OF NOTRE DAME DU LAC
Reel/Frame 060831/0542 →
Continuity (4)
Division 16560336 · Sep 4, 2019
Continuation 15501919
Provisional Application 62048561 · Sep 10, 2014
Related Publication 20220249634A1 · Aug 11, 2022
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