Conditional superagonist CTL ligands for the promotion of tumor-specific CTL responses
View Patent ↗What is described is a novel genetic screen, involving recombinant technology and class I antigen cross-presentation, to search for supraoptimal superagonists of the 27L MART-1 mutant selecting for single amino acid substitution mutants of 27L that activate human antigen-specific CTL clones recognizing the wild-type MART-1 26-35 epitope. Three novel mutant epitopes are identified with superagonist properties that are functionally superior to 27L. The ability of a given analog to act as superagonist varies among patients. Also described is the use of methods to establish panels of potential superagonist APLs to individualize tumor peptide vaccines among patients. The methodology is replicated to identify APL to NY-ESO-1 157-165 and NY-ESO-1 157-170 tumor epitopes. A general method is described that is useful to produce a tumor vaccine to any tumor epitope.
1. A compound for the treatment of a patient with a tumor, wherein the compound comprises a peptide comprising a tumor epitope, wherein the tumor epitope comprises an amino acid substitution in a tumor antigen, wherein the tumor antigen is SEQ ID NO: 144 or 228, and wherein the compound comprises a sequence selected from the group consisting of SEQ ID NOS: 362-365 and 368-376.
2. The compound of claim 1 , wherein the peptide is produced by an expression vector in a host cell in vitro wherein the expression vector comprises a nucleotide sequence selected from the group consisting of SEQ ID NO: 377-391.
3. The compound of claim 2 , where the nucleotide sequence is expressed in human cells.
4. The compound of claim 3 , wherein the nucleotide sequence is expressed in cells obtained from a melanoma patient.
5. The compound of claim 1 , wherein the tumor antigen is SEQ ID NO: 144, and wherein the compound comprises a sequence selected from the group consisting of SEQ ID NOS: 368-376.
6. The compound of claim 5 , wherein the peptide is produced by an expression vector in a host cell in vitro wherein the expression vector comprises a nucleotide sequence selected from the group consisting of SEQ ID NO: 382-391.
7. The compound of claim 5 , wherein the compound comprises a sequence consisting of SEQ ID NOS: 372, 374, or 375.
8. The compound of claim 1 , wherein the tumor antigen is SEQ ID NO: 228, and the compound comprises a sequence selected from the group consisting of SEQ ID NOS: 362-365.
9. The compound of claim 8 , wherein the peptide is produced by an expression vector in a host cell in vitro wherein the expression vector comprises a nucleotide sequence selected from the group consisting of SEQ ID NOS: 377-381.
10. The compound of claim 8 , wherein the tumor antigen is SEQ ID NO: 228, and the compound comprises a sequence consisting of SEQ ID NOS: 362, 363 or 365.
11. The compound of claim 1 , wherein the wherein the compound comprises a multiplicity of sequences selected from the group consisting of SEQ ID NOS: 362-365 and 368-376.
12. The compound of claim 11 , wherein the wherein the compound comprises a multiplicity of sequences selected from the group consisting of SEQ ID NOS: 362-365.
13. The compound of claim 12 , wherein the compound comprises a sequence consisting of SEQ ID NOS: 362, 363 or 365.
14. The compound of claim 11 , wherein the wherein the compound comprises a multiplicity of sequences selected from the group consisting of SEQ ID NOS: 368-376.
15. The compound of claim 14 , wherein the compound comprises a sequence consisting of SEQ ID NOS: 372, 374, or 375.