#4 - Human monoclonal Antibody Based Cancer Therapies
Title: Human monoclonal antibody targeted to mesothelin for the treatment of cancer
NIH Reference No.: E-236-2012
Executive Summary
*Special Note: For this invention, breast cancer is the only field of use available for the start-up phase of the challenge. Teams may use the background data associated with this invention related to other cancers in order to fully understand the toxicology, efficacy, and other scientific parameters as well as to understand how the commercialization, development and regulatory landscape may evolve based on the invention as a whole
General Description
Mesothelin is a cell surface protein that is highly expressed in aggressive cancers such as malignant mesothelioma, ovarian cancer, pancreatic cancer, lung cancer, breast cancer, cholangiocarcinoma, bile duct carcinoma and gastric cancer. This selective expression makes mesothelin an excellent candidate for targeted therapeutics such as monoclonal antibodies (mAbs) and corresponding chimeric molecules. A mAb is a molecule that is generated in the lab and engineered to attach to specific targets in cancer cells. They mimic the antibodies naturally produced as part of the immune system's response to germs, vaccines and other invaders. The mAbs bind to the target and trigger the immune system to attack the target. Although a number of anti-mesothelin mAbs are currently in the clinic, many of them have drawbacks, such as competition with a serum protein (MUC16/CA125) for binding to mesothelin, the formation of neutralizing antibodies because they are non-human antibodies, and the inability to trigger complement-dependent cytotoxicity (CDC). CDC has been suggested as an important additional mechanism for cancer therapeutic antibodies. Although high hopes remain that a therapeutic agent will ultimately be developed using the current clinical candidates, improvements may be necessary to develop effective anti-mesothelin antibody-based therapeutics
Scientific Progress
NIH inventors have generated two single domain human mAbs called SD1 and SD2. SD1 recognizes a unique epitope in region III of mesothelin which is not out-competed for binding by MUC16/CA125 which should increase the efficacy of the antibody. In addition, SD1 is capable of triggering CDC, as well as antibody-dependent cellular cytotoxicity (ADCC). Both ADCC and CDC are thought to be important mechanisms for therapeutic antibodies in cancer treatment. Due to its human origin, SD1 is also less likely to elicit the formation of neutralizing antibodies when administered to patients. The combination of these characteristics suggests that SD1 may be an effective therapeutic agent. In mouse xenograft models using an A431 human epithelial carcinoma cell line that over-expresses human mesothelin, SD1 was able to inhibit tumor growth with an average tumor size of 300 mm3 compared to 1000 mm3 in the control group. The corresponding immunotoxins also showed inhibition of tumor cell growth in vitro. In addition to the therapeutic uses, the antibody also has a potential use in a diagnostic kit to detect the presence of mesothelin in tumor tissue
Future Work
Strengths
Weaknesses
Patent Status
Provisional U.S. Application No. 61/706,396 filed September 27, 2012
PCT Application in Preparation
Relevant Publications
Hassan, R., et al. Eur J Cancer, 2008 [PMID: 17945478]
Tang, Z.,et al. Mol Cancer Ther, 2013 [PMID: 23371858]
Inventor Bio
Mitchell Ho, Ph.D.
Dr. Ho received his Ph.D. as a National Research Service Award fellow under Dr. Mariangela Segre from the University of Illinois at Urbana-Champaign, where he developed monoclonal antibodies against cocaine. He was a postdoctoral fellow in the laboratory of Dr. Ira Pastan at the NIH and generated immunotoxins directed against cancer. He also conducted research at PDL BioPharma and DNAX (now Merck Research Labs), where he developed an interest in phage display antibody engineering and high-throughput flow cytometry technologies. Dr. Ho is a recipient of the 2011 NCI Director's Intramural Innovation Award for Principal Investigators, the Mesothelioma Applied Research Foundation Grant Award, and the Ovarian Cancer Research Fund Individual Investigator Award. He is Chair of the NIH Antibody Interest Group, and he is on the Antibody Society's Board of Distinguished Advisors. He has served on the editorial boards of peer-reviewed journals. He has also served on grant review panels for NIH and DOD as well as major cancer foundations. Dr. Ho regularly presents at international symposia and is a member of the organizing committees for several international conferences on therapeutic antibodies
NIH Reference No.: E-236-2012
Executive Summary
- Category: Therapeutic, Diagnostic
- Disease Focus: Applicable to many cancer types (breast, liver, pancreas, mesothelioma, ovarian) but limited to breast cancer for the Challenge
- Basis of Invention: Antibody
- How it works: Binds specifically to a target on cancer cells and inhibits the growth of tumors
- Patent Status: U.S. Patent pending
- Lead Inventor: Mitchell Ho, Ph.D.
- Development Stage: In vitro inhibition of tumor cell growth; Evaluated in mouse xenograft models
- Novelty: Fully human monoclonal antibody which targets a different region of mesothelin than the current clinical candidates
- Clinical Application: As a cancer therapeutic either alone or in combination. Potential use in antibody-drug conjugates or in vaccines. Potential use in generation of a diagnostic kit for mesothelin-expressing cancers
*Special Note: For this invention, breast cancer is the only field of use available for the start-up phase of the challenge. Teams may use the background data associated with this invention related to other cancers in order to fully understand the toxicology, efficacy, and other scientific parameters as well as to understand how the commercialization, development and regulatory landscape may evolve based on the invention as a whole
General Description
Mesothelin is a cell surface protein that is highly expressed in aggressive cancers such as malignant mesothelioma, ovarian cancer, pancreatic cancer, lung cancer, breast cancer, cholangiocarcinoma, bile duct carcinoma and gastric cancer. This selective expression makes mesothelin an excellent candidate for targeted therapeutics such as monoclonal antibodies (mAbs) and corresponding chimeric molecules. A mAb is a molecule that is generated in the lab and engineered to attach to specific targets in cancer cells. They mimic the antibodies naturally produced as part of the immune system's response to germs, vaccines and other invaders. The mAbs bind to the target and trigger the immune system to attack the target. Although a number of anti-mesothelin mAbs are currently in the clinic, many of them have drawbacks, such as competition with a serum protein (MUC16/CA125) for binding to mesothelin, the formation of neutralizing antibodies because they are non-human antibodies, and the inability to trigger complement-dependent cytotoxicity (CDC). CDC has been suggested as an important additional mechanism for cancer therapeutic antibodies. Although high hopes remain that a therapeutic agent will ultimately be developed using the current clinical candidates, improvements may be necessary to develop effective anti-mesothelin antibody-based therapeutics
Scientific Progress
NIH inventors have generated two single domain human mAbs called SD1 and SD2. SD1 recognizes a unique epitope in region III of mesothelin which is not out-competed for binding by MUC16/CA125 which should increase the efficacy of the antibody. In addition, SD1 is capable of triggering CDC, as well as antibody-dependent cellular cytotoxicity (ADCC). Both ADCC and CDC are thought to be important mechanisms for therapeutic antibodies in cancer treatment. Due to its human origin, SD1 is also less likely to elicit the formation of neutralizing antibodies when administered to patients. The combination of these characteristics suggests that SD1 may be an effective therapeutic agent. In mouse xenograft models using an A431 human epithelial carcinoma cell line that over-expresses human mesothelin, SD1 was able to inhibit tumor growth with an average tumor size of 300 mm3 compared to 1000 mm3 in the control group. The corresponding immunotoxins also showed inhibition of tumor cell growth in vitro. In addition to the therapeutic uses, the antibody also has a potential use in a diagnostic kit to detect the presence of mesothelin in tumor tissue
Future Work
- NIH inventors plan to optimize SD1 through protein engineering of a variety of biophysical properties including increased affinity and improved serum half-life. SD1 will be further examined in a variety of tumor models. In addition, the cytotoxic drug/toxin conjugates based on SD1 will be constructed and tested for potentially better anti-tumor activity
Strengths
- Fully humanized antibody reduces the possibility of neutralization
- Novel binding site for antibodies with induction of both ADCC and CDC
- Demonstrated inhibition of tumor growth in mouse xenograft models
Weaknesses
- Additional animal studies are needed using other cancer cell lines
Patent Status
Provisional U.S. Application No. 61/706,396 filed September 27, 2012
PCT Application in Preparation
Relevant Publications
Hassan, R., et al. Eur J Cancer, 2008 [PMID: 17945478]
Tang, Z.,et al. Mol Cancer Ther, 2013 [PMID: 23371858]
Inventor Bio
Mitchell Ho, Ph.D.
Dr. Ho received his Ph.D. as a National Research Service Award fellow under Dr. Mariangela Segre from the University of Illinois at Urbana-Champaign, where he developed monoclonal antibodies against cocaine. He was a postdoctoral fellow in the laboratory of Dr. Ira Pastan at the NIH and generated immunotoxins directed against cancer. He also conducted research at PDL BioPharma and DNAX (now Merck Research Labs), where he developed an interest in phage display antibody engineering and high-throughput flow cytometry technologies. Dr. Ho is a recipient of the 2011 NCI Director's Intramural Innovation Award for Principal Investigators, the Mesothelioma Applied Research Foundation Grant Award, and the Ovarian Cancer Research Fund Individual Investigator Award. He is Chair of the NIH Antibody Interest Group, and he is on the Antibody Society's Board of Distinguished Advisors. He has served on the editorial boards of peer-reviewed journals. He has also served on grant review panels for NIH and DOD as well as major cancer foundations. Dr. Ho regularly presents at international symposia and is a member of the organizing committees for several international conferences on therapeutic antibodies