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Cancer Vaccine Based On Triggering an Immune Response to Pappalysin, with Utility Anticipated Especially in Prostate Cancer and Lung Cancer
University of York United Kingdom flag United Kingdom
Abstract ID:
Pappalysin is highly expressed in prostate cancer stem cells and in prostate cancer cell lines but shows very limited, low level expression in normal male tissues. Among other actions, its ablation is predicted to reduce aberrant activation of insulin-lik...
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Pappalysin is a secreted pregnancy associated metalloproteinase of molecular weight 181 kilodaltons which naturally exists as a disulphide linked homodimer which is expressed continually during pregnancy and is found in a complex with an inhibitor protein called eosinophil major basic protein in a 2:2 proteinase:inhibitor complex. A second form of the enzyme exists as pappalysin 2 [PappA2] which has a molecular weight of 198.5 kilodaltons, functions as a monomer and is preferentially expressed in the placenta and non-pregnant mammary gland with low expression in the kidney, fetal brain and pancreas.

The substrates for pappalysin are insulin like growth factor binding proteins [IGFBP] of which there are 6 different proteins. IGFBP 4 and 5 are the preferred substrates for pappalysin. PappA2 cleaves IGFBP 5 preferentially.

IGFBPs are found tightly bound with insulin-like growth factor [IGF-1] which inhibits insulin-like growth factor I (IGF-1) activity. IGF-1 is a 70 amino acid polypeptide with a molecular weight of 7.61 (D. IGF-1 stimulates, amongst other cells, the proliferation of chondrocytes resulting in bone growth. IGF-1 is also implicated in muscle development. IGF-1 is an example of a protein ligand that interacts with members of the receptor tyrosine kinase (RTK) superfamily. Approximately 98% of IGF-1 is bound to one of the six IGFBPs. IGFBP3 is the most abundant and accounts for 80% of IGF-1 binding. IGF-1 binds two receptors; the IGF-1 receptor (IGFR) and insulin receptor (IR) the former of which is bound with greater affinity. It is also known that IGF-1 has a role in the maintenance of tumours and therefore IGF-1 antagonists will have therapeutic value in the treatment of cancer.

The USA patent application received a Notice of Allowance, on 19.03.2014 with prevailing claims as follows:

1. An immunogenic composition comprising an antigenic pappalysin polypeptide fragment and an adjuvant and/or carrier, wherein the antigenic pappalysin polypeptide consists of the amino acid sequence set forth in SEQ ID NO: 26.

2-4. (Canceled).

5. (Currently Amended) A [[DNA]] composition comprising a nucleic acid molecule encoding an antigenic pappalysin polypeptide fragment wherein when said nucleic acid molecule is expressed the antigenic pappalysin polypeptide fragment consists consisting of the amino acid sequence set forth in SEQ ID NO:26 is produced.

6-8. (Canceled).

9. (Currently Amended) The [[DNA]] composition of claim 5 wherein the nucleic acid molecule is part of an expression vector adapted to express the antigenic pappalysin polypeptide fragment.

10. The composition of claim 1 wherein the adjuvant is a cytokine selected from the group-consisting of GMCSF (granulocyte colony-stimulating factor) , interferon gamma, interferon alpha, interferon beta, interleukin 12, interleukin 23, interleukin 17, interleukin 2, interleukin 1, TGF (transforming growth factor), TNFa (tumor necrosis factor alpha), and TNFJ3 (tumor necrosis factor beta).

11. The composition claim 1 wherein the adjuvant is a TLR (toll-like receptor) agonist.

12. The composition of claim 11 wherein the TLR agonist is selected from the group consisting of: CpG oligonucleotides, flagellin, monophosphoryl lipid A, poly I:C and derivatives thereof.

13. The composition of claim 12 wherein the adjuvant is a CpG oligonucleotide.

14. The composition of claim 1 wherein the adjuvant is a bacterial cell wall derivative selected from the group consisting of muramyl dipeptide (MDP) and trehelose dycorynemycolate TDM).

15. A method of vaccinating a subject suffering from or having a predisposition to cancer comprising administering an effective amount of an immunogenic composition comprising an antigenic pappalysin polypeptide fragment and an adjuvant and/or carrier wherein the antigenic pappalysin polypeptide fragment consists of the amino acid sequence set forth in SEQ ID NO:26.

16. The method of claim 15 wherein the cancer is prostate cancer.

17. The method of claim 15 wherein the cancer is lung cancer.

The EPO patent application has been subject to a first examination and the prevailing claims are as follows:

1. A vaccine composition comprising a pappalysin antigenic part consisting of an amino acid sequence presented in Figure 14d, or a variant antigenic part having at least 75% sequence identity to the amino acid sequence in Figure 14d, and an adjuvant and/or carrier.

2. The vaccine composition according to claim 1 wherein said antigenic fragment consists of the amino acid sequence presented in Figure 14d.

3. A DNA vaccine composition comprising a nucleic acid molecule encoding a pappalysin antigenic part consisting of the nucleic acid sequence presented in Figure 12d.

4. A DNA vaccine according to claim 3 wherein said nucleic acid molecule is part of an expression vector adapted to express said pappalysin polypeptide of antigenic part thereof.

5. A composition according to any of claims 1-4 wherein said adjuvant is selected from the group consisting of: cytokines selected from the group consisting of GMCSF, interferon gamma, interferon alpha, interferon beta, interleukin 12, interleukin 23, interleukin 17, interleukin 2, interleukin 1, TGF, TNFα, and TNFβ.

6. A composition according to any of claims 1-4 wherein adjuvant is a TLR agonist.

7. A composition according to claim 6 wherein said TLR agonist is selected from the group consisting of: CpG oligonucleotides, flagellin, monophosphoryl lipid A, poly I:C and derivatives thereof.

8. A composition according to claim 7 wherein said adjuvant is a CpG oligonucleotide.

9. A composition according to any of claims 1-4 wherein said adjuvant is a bacterial cell wall derivative such as muramyl dipeptide (MDP) and/or trehelose dycorynemycolate (TDM).

10. A vaccine composition according to any one claims 1-9 for use in treatment of cancer.
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FEATURED
Last Updated Oct 2014
Technology Type THERAPEUTIC
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UNIVERSITY