Marker Therapeutics Inc (MRKR)

[Rkmatters]

I hadn't been holding at this point. But only because LIncoln Park Capital still had shares to sell, and I thought I could get a dip. Really sad day for them today.

GALE has major shortcomings. No helper

HER-2/neu antigen is a 23-mer, p362–384, QEFAGCKKIFGSLAFLPESFDGD.

Peptides are fragments. But, some peptides are better than others.

GALE's HER2-neu peptide is a 9-mer epitope, p369-377 (KIFGSLAFL), and is processed from larger 23-mer HER-2/neu derived fragments. It was one of first antigens discovered, in 1995. It was in Phase III testing, but I've written that it's shortcomings is that the immune response is not long-lasting, and the vaccine does not elicit immune memory, as it did not contain any helper component to the vaccine. The trial was using booster shots so I was hopefully it would get around that. As we now know it didn't and the trial was stopped for futility.

Unfortunate day today.

TPIV's HER2-neu peptide is a 10-mer epitope p373-382 (SLAFLPESFD) and is also processed from larger 23-mer HER-2/neu derived fragments (above).

Mayo's proprietary HER2 antigens, licensed to TPIV, were discovered by Keith Knutson Ph.D. and colleagues using a series of computer based predictions followed by testing of breast cancer patient responses to the predicted target peptides. Importantly this immune response data indicates that these antigens are naturally processed and that tolerance to these self-antigens is not a limiting factor. The peptides show high affinity binding to human MHC proteins for 84% of the population, making this potentially applicable to a wider spectrum of patients when compared to other HER-2/neu vaccine compositions.

There are two requirements needed to create a good immune response: 

1) HLA Class 1 pathway: stimulate the cytotoxic lymphocyte, CD8 (killer T-cells) that will infiltrate and destroy tumor cells  -- MAYO PRECLINICAL TESTING p373-382. NeuVax had this.

2) HLA Class 2 pathway: stimulate the pathway that stimulates the CD4 (T helper cells) for a prolonged immune response.  -- TESTED in PHASE I -- TPIV-100. Missing in GALE's Neu-Vax

Mayo's technology, again licensed to TPIV, have them both.  They plan to combine into the next TPIV Clinical Trial Phase Ib/II (4 helper T antigens + 1 Killer T HER-2 neu (p373-382)) Strategy: 

Class II helper antigens (TPIV100: 4 epitopes [HER-neu.p59, p88, p422, p885]) from Phase l
+
Class I Killer T Cell antigen (p373-382): Mayo's Superior Killer T Cell Epitope*

"Naturally processed killer T-cell epitope (p373-382)
Log order increased binding to HLA-A2
Higher class I expression on human A2 cells
4-5x killing efficacy of human breast cancer cells
    * Compared to E-75 (Neuvax). J. Immunol. (2013) 190, 479-488)"

More specifics on the difference between p369-377 (GALE) and p373-382 (TPIV). But you can see what the right expression on the cell can do. Not all vaccines are created equal.

J Immunol. 2013 Jan 1;190(1):479-88. doi: 10.4049/jimmunol.1201264. Epub 2012 Nov 23.
Enzymatic discovery of a HER-2/neu epitope that generates cross-reactive T cells.
 
Henle AM1, Erskine CL, Benson LM, Clynes R, Knutson KL.

Abstract
Patients with HER-2/neu-expressing breast cancer remain at risk for relapse following standard therapy. Vaccines targeting HER-2/neu to prevent relapse are in various phases of clinical testing. Many vaccines incorporate the HER-2/neu HLA-A2-binding peptide p369-377 (KIFGSLAFL), because it has been shown that CTLs specific for this epitope can directly kill HER-2/neu-overexpressing breast cancer cells. Thus, understanding how tumors process this epitope may be important for identifying those patients who would benefit from immunization. Proteasome preparations were used to determine if p369-377 was processed from larger HER-2/neu-derived fragments. HPLC, mass spectrometry, cytotoxicity assays, IFN-? ELISPOT, and human breast cancer cell lines were used to assess the proteolytic fragments. Processing of p369-377 was not detected by purified 20S proteasome and immunoproteasome, indicating that tumor cells may not be capable of processing this Ag from the HER-2/neu protein and presenting it in the context of HLA class I. Instead, we show that other extracellular domain HER-2/neu peptide sequences are consistently processed by the proteasomes. One of these sequences, p373-382 (SLAFLPESFD), bound HLA-A2 stronger than did p369-377. CTLs specific for p373-382 recognized both p373-382 and p369-377 complexed with HLA-A2. CTLs specific for p373-382 also killed human breast cancer cell lines at higher levels than did CTLs specific for p369-377. Conversely, CTLs specific for p369-377 recognized p373-382. Peptide p373-382 is a candidate epitope for breast cancer vaccines, as it is processed by proteasomes and binds HLA-A2.

Full article of part of Mayo-TPIV new epitope: 

www.ncbi.nlm.nih.gov/pmc/articles/PMC3529812/