Mesothelioma is an aggressive but rare form of cancer with a poor prognosis. 1-year survival is ~40% and 5-year survival remains in single digits. Treatment involves a combination of surgery, chemotherapy, and radiation therapy. Mesothelioma is a disease with unmet medical needs and deserving development of novel targeted therapies. Our laboratory is focused on developing novel antibodies useful in treating rare cancers such as mesothelioma. We have raised a mouse antibody library against human cancer cell surface proteins (CSPs). Antibodies were screened against several cancer cells including mesothelioma to identify antibodies specific for cancer CSP as druggable candidates. Screening identified antibodies that bound to and internalized into cancer cells. Such candidates were further characterized. One such antibody (AG02) was identified as having superior binding and internalization characteristics to the other antibodies. The therapeutic potential of AG02 was established as follows; 1) the cell surface protein named CSP-1 against which AG02 bound on the cell surface of selected cancer cells was identified by immunoprecipitation followed by mass spectrometry. Identified CSP-1 was demonstrated as being associated with metastatic potential thus emphasizing its potential as an important target for development of an anti-cancer agent; 2) We demonstrated that upon binding to CSP-1, AG02 antibody internalized the CSP-1 target; 3) We confirmed that AG02 antibody was first-in-class as no other internalizing antibody to this CSP-1 had been developed; 4) Since AG02 is an internalizing antibody, we developed ADC by conjugating AG02 to a generic cytotoxic drug saporin, routinely used as a cost-effective payload in ADCs for proof-of-concept (POC) study. Our POC AG02ADC was tested against a panel of cancer cells and found to bind strongly to CSPs in several cancers with orphan status and unmet needs including mesothelioma. In vitro and in vivo studies established that: (1) AG02 conjugated to saporin at 10nM was able to kill cells expressing CSP while it did not kill non-CSP-1 expressing cells, natural or transfected. (2) AG02-ADC acted in a dose dependent fashion, (3) when tested against different know cancer cell types, AG02-ADC killed >50% of cancer cells while a non-specific mouse IgG-ADC or Drug alone had no effect. (4) Using AG02-ADC treatment in nude mice, we demonstrated tumor growth inhibition >50% in several xenografts. While saporin was used in these studies as payload and shows efficacy, we expect more potent drugs such as MMAE or DM1 to have considerably more efficacy. In summary, we have demonstrated that: AG02 is specific for a CSP-1 overexpressed in certain cancers and involved in metastasis; AG02 is internalized in CSP-1 expressing natural cancer cells; AG02-ADC kills CSP-1 expressing cancer cells. Targeting mesothelioma may enable AG02-ADC to benefit of the FDA’s Orphan Drug Program as it nears drug and clinical development.
Citation Format: Jorge Marquez, Chun Dong, Jianping Dong, Binbin Yue, Ginette Serrero. Novel antibody drug conjugate to inhibit mesothelioma tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 210.