Preclinical Development of an Anti-NaPi2b (SLC34A2) Antibody-Drug Conjugate as a Therapeutic for Non-Small Cell Lung and Ovarian Cancers.

Abstract

PURPOSE:

Antibody-drug conjugates (ADC) selectively deliver a cytotoxic drug to cells expressing an accessible antigenic target. Here, we have appended monomethyl auristatin E (MMAE) to an antibody recognizing the SLC34A2 gene product NaPi2b, the type II sodium-phosphate cotransporter, which is highly expressed on tumor surfaces of the lung, ovary, and thyroid as well as on normal lung pneumocytes. This study evaluated its efficacy and safety in preclinical studies.

EXPERIMENTAL DESIGN:

The efficacy of anti-NaPi2b ADC was evaluated in mouse ovarian and non-small cell lung cancer (NSCLC) tumor xenograft models, and its toxicity was assessed in rats and cynomolgus monkeys.

RESULTS:

We show here that an anti-NaPi2b ADC is effective in mouse ovarian and NSCLC tumor xenograft models and well-tolerated in rats and cynomolgus monkeys at levels in excess of therapeutic doses. Despite high levels of expression in normal lung of non-human primate, the cross-reactive ADC exhibited an acceptable safety profile with a dose-limiting toxicity unrelated to normal tissue target expression. The nonproliferative nature of normal pneumocytes, together with the antiproliferative mechanism of MMAE, likely mitigates the potential liability of this normal tissue expression.

CONCLUSIONS:

Overall, our preclinical results suggest that the ADC targeting NaPi2b provides an effective new therapy for the treatment of NSCLC and ovarian cancer and is currently undergoing clinical developments.

• Authors: Kedan Lin, Bonnee Rubinfeld, Crystal Zhang, Ron Firestein, Eric Harstad, Leslie Roth, Siao Ping Tsai, Melissa Schutten, Keyang Xu, Maria Hristopoulos, Paul Polakis
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 22 Pg. 5139-50 (Nov 15 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 26156394 (Publication Type: Journal Article)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal
• Immunoconjugates
• Oligopeptides
• Slc34a2 protein, mouse
• Sodium-Phosphate Cotransporter Proteins, Type IIb
• monomethyl auristatin E

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage)
• Carcinoma, Non-Small-Cell Lung (drug therapy, immunology, pathology)
• Female
• Humans
• Immunoconjugates (administration & dosage)
• Macaca fascicularis
• Male
• Mice
• Oligopeptides (administration & dosage, immunology)
• Ovarian Neoplasms (drug therapy, immunology, pathology)
• Rats
• Sodium-Phosphate Cotransporter Proteins, Type IIb (antagonists & inhibitors, immunology)
• Xenograft Model Antitumor Assays