In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4815-4815
Abstract:
Background: Globo H, a hexasaccharide, has been reported to be highly expressed in multiple cancers types, but not express or, if at all, express to a lesser extent in normal tissue. Therefore, Globo H may be a potential target for cancer immunotherapy. OBI-999 is an antibody-drug conjugate (ADC) which consists of a Globo H-specific monoclonal antibody OBI-888, conjugated with monomethyl auristatin E (MMAE), a synthetic antineoplastic agent. The present study investigates antigen specificity, drug internalization, anti-tumor efficacy, and pharmacokinetics profiles of OBI-999. Methods: Globo H expression was surveyed in various human cancer cell lines. The binding specificity and internalization of OBI-999 were determined by flow cytometry and confocal microscopy, respectively. In vivo anti-tumor efficacy was studied in conventional xenograft and patient-derived xenograft models. Pharmacokinetic parameters were evaluated in normal and tumor bearing xenograft mice. Results: We confirmed positive Globo H expression on the cell surface of multiple cancer cell lines ranging from breast, gastric, lung, to pancreatic cancer. From flow cytometry, OBI-999 showed binding selectivity to the aforementioned Globo H expressing cell lines. In contrast, OBI-999 did not bind to non-Globo H expressing cell lines. When bound to the antigen, OBI-999 was internalized and trafficked to endosome and lysosome within 2.5 to 5 hours, suggesting that the drug payload, MMAE, was cleaved in a lysosome dependent manner. OBI-999 showed significant tumor inhibition in breast, gastric, lung, and pancreatic cancer xenograft and PDX models in dose-dependent manner. At 1 mg/kg of OBI-999, tumor growth inhibition in breast, gastric, and lung cancer model were 77%, 89%, and 68% respectively. At 10 mg/kg of OBI-999, complete tumor growth inhibition in pancreatic cancer model was observed. In vitro serum stability studies revealed that OBI-999 has comparable stabilities to Adcetris® in mouse, rat, monkey, and human sera. Tissue distribution study revealed that OBI-999 is accumulated gradually at the tumor site while the level of OBI-999 showed a time dependent decrease in blood-rich organs. Accumulation of OBI-999 at the tumor site reached its maximum level at 168 hour post treatment. Level of MMAE in tumor mass was approximately 25 folds higher than that in other organs and 250 folds higher than that in serum, suggesting that OBI-999 targets and releases its payload at tumor region. Conclusion: The preclinical studies of OBI-999 demonstrated its targeting specificity and anti-tumor efficacy in multiple Globo H positive cancer models. OBI-999 also demonstrated a longer retention at tumor site. The preclinical results provided the fundamental basis for OBI-999’s clinical application as targeted cytotoxicity therapy for solid tumors. Citation Format: Ming-Chen Yang, Yu-Jung Chen, Chi-Sheng Shia, Hui-Wen Chang, Wan-Fen Li, Cheng-Der Tony Yu, I-Ju Chen. Novel Globo H targeting antibody-drug conjugate with binding specificity and anti-tumor efficacy in multiple cancer types [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 4815.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2019-4815
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2019
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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