Cancer targeted innate immunity
Patent Number: US9522958
Executive Summary:
Most tumors express antigens that can be recognized to a variable extent by the host immune system, but in many cases, the immune response is inadequate. Immunotherapies solely relying on T cell or antibody activity work poorly in tumors with low antigen expression. Therefore, activation of the innate immune system offers the opportunity to combat a wider range of cancer cases. CpG oligodeoxynucleotides (CpG) potently activate the immune system by mimicking microbial DNA. Conjugation of CpG to chTNT-3, an antibody targeting the necrotic centers of tumors, enabled CpG to accumulate in tumors after systemic delivery, where it can activate the immune system in the presence of tumor antigens. The systemic use of CpG immunoconjugates is a step forward in the employment of innate immunity for cancer treatment.
Scientific Progress:
chTNT-3/CpG delayed tumor growth and improved survival in tumors of varying immunogenicities, including poorly immunogenic models MAD109, Lewis lung carcinoma, and B16 (ref. 1).
Future Directions:
Jang JK, Khawli LA, Canter DC, Hu P, Zhu TH, Wu BW, Angell TE, Li Z, Epstein AL. Systemic delivery of chTNT-3/CpG immunoconjugates for immunotherapy in murine solid tumor models. Cancer Immunol Immunother. 2016 May;65(5):511-23. doi:10.1007/s00262-016-1813-x. Epub 2016 Mar 9. PubMed PMID: 26960932; PubMed Central PMCID: PMC4841721.
Li Z, Jang JK, Lechner MG, Hu P, Khawli L, Scannell CA, Epstein AL. Generation of tumor-targeted antibody-CpG conjugates. J Immunol Methods. 2013 Mar 29;389(1-2):45-51. doi:10.1016/j.jim.2012.12.009. Epub 2012 Dec 29. PubMed PMID: 23279945.
Lechner MG, Epstein AL. A new mechanism for blocking myeloid-derived suppressor cells by CpG. Clin Cancer Res. 2011 Apr 1;17(7):1645-8. doi:10.1158/1078-0432.CCR-11-0024. Epub 2011 Feb 2. PubMed PMID: 21288925; PubMed Central PMCID: PMC4237605.
Inventor Bio: Alan L. Epstein
http://keck.usc.edu/faculty/alan-l-epstein/
Executive Summary:
- Invention Type: Therapeutic
- Patent Status: US grant, Active
- Patent Link: https://patents.google.com/patent/US9522958/
- Research Institute: University of Southern California
- Disease Focus: Cancer
- Basis of Invention: The innate immune system is directed to recognition of invariant molecular structures in pathogens. CpG motifs, which consist of unmethylated CG dinucleotides arranged in a specific sequence and framework, represent an example of the structure triggering the innate immune response
- How it works: A cancer targeting molecule, for example, an antibody specific for a tumor antigen, is linked to a synthetic DNA oligonucleotide containing the CpG motif. The CpG motif triggers innate immune response at the tumor site
- Lead Challenge Inventor: Alan L. Epstein
- Inventors: Alan L. Epstein, Leslie A. Khawli
- Development Stage: Pre-clinical: in vivo data in mouse model of colon cancer
- Novelty:
- Utilization of innate immune response in cancer treatment
- Conjugation of CpG motif to cancer-specific antibody for targeted activation of the innate immune response
- Clinical Applications:
- Immunotherapy of cancers with low immunogenicity
Most tumors express antigens that can be recognized to a variable extent by the host immune system, but in many cases, the immune response is inadequate. Immunotherapies solely relying on T cell or antibody activity work poorly in tumors with low antigen expression. Therefore, activation of the innate immune system offers the opportunity to combat a wider range of cancer cases. CpG oligodeoxynucleotides (CpG) potently activate the immune system by mimicking microbial DNA. Conjugation of CpG to chTNT-3, an antibody targeting the necrotic centers of tumors, enabled CpG to accumulate in tumors after systemic delivery, where it can activate the immune system in the presence of tumor antigens. The systemic use of CpG immunoconjugates is a step forward in the employment of innate immunity for cancer treatment.
Scientific Progress:
chTNT-3/CpG delayed tumor growth and improved survival in tumors of varying immunogenicities, including poorly immunogenic models MAD109, Lewis lung carcinoma, and B16 (ref. 1).
Future Directions:
- Clinical trials
- Robust and convincing pre-clinical data
- Filing date: 2011-09-08
- Publication date and Grant date: 2016-12-20
- Other versions: US20120076804A1 (Application)
Jang JK, Khawli LA, Canter DC, Hu P, Zhu TH, Wu BW, Angell TE, Li Z, Epstein AL. Systemic delivery of chTNT-3/CpG immunoconjugates for immunotherapy in murine solid tumor models. Cancer Immunol Immunother. 2016 May;65(5):511-23. doi:10.1007/s00262-016-1813-x. Epub 2016 Mar 9. PubMed PMID: 26960932; PubMed Central PMCID: PMC4841721.
Li Z, Jang JK, Lechner MG, Hu P, Khawli L, Scannell CA, Epstein AL. Generation of tumor-targeted antibody-CpG conjugates. J Immunol Methods. 2013 Mar 29;389(1-2):45-51. doi:10.1016/j.jim.2012.12.009. Epub 2012 Dec 29. PubMed PMID: 23279945.
Lechner MG, Epstein AL. A new mechanism for blocking myeloid-derived suppressor cells by CpG. Clin Cancer Res. 2011 Apr 1;17(7):1645-8. doi:10.1158/1078-0432.CCR-11-0024. Epub 2011 Feb 2. PubMed PMID: 21288925; PubMed Central PMCID: PMC4237605.
Inventor Bio: Alan L. Epstein
http://keck.usc.edu/faculty/alan-l-epstein/