Preclinical development of an anti-NaPi2b (SLC34A2) antibody-drug conjugate as a therapeutic for non-small cell lung and ovarian cancers

Kedan Lin, Bonnee Rubinfeld, Crystal Zhang, Ron Firestein, Eric Harstad, Leslie Roth, Siao Ping Tsai, Melissa Schutten, Keyang Xu, Maria Hristopoulos, Paul Polakis

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27 Citations (Scopus)

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 crossreactive 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.

Original languageEnglish
Pages (from-to)5139-5150
Number of pages12
JournalClinical Cancer Research
Volume21
Issue number22
DOIs
Publication statusPublished - 15 Nov 2015
Externally publishedYes

Cite this

Lin, Kedan ; Rubinfeld, Bonnee ; Zhang, Crystal ; Firestein, Ron ; Harstad, Eric ; Roth, Leslie ; Tsai, Siao Ping ; Schutten, Melissa ; Xu, Keyang ; Hristopoulos, Maria ; Polakis, Paul. / Preclinical development of an anti-NaPi2b (SLC34A2) antibody-drug conjugate as a therapeutic for non-small cell lung and ovarian cancers. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 22. pp. 5139-5150.
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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 crossreactive 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.",
author = "Kedan Lin and Bonnee Rubinfeld and Crystal Zhang and Ron Firestein and Eric Harstad and Leslie Roth and Tsai, {Siao Ping} and Melissa Schutten and Keyang Xu and Maria Hristopoulos and Paul Polakis",
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Lin, K, Rubinfeld, B, Zhang, C, Firestein, R, Harstad, E, Roth, L, Tsai, SP, Schutten, M, Xu, K, Hristopoulos, M & Polakis, P 2015, 'Preclinical development of an anti-NaPi2b (SLC34A2) antibody-drug conjugate as a therapeutic for non-small cell lung and ovarian cancers', Clinical Cancer Research, vol. 21, no. 22, pp. 5139-5150. https://doi.org/10.1158/1078-0432.CCR-14-3383

Preclinical development of an anti-NaPi2b (SLC34A2) antibody-drug conjugate as a therapeutic for non-small cell lung and ovarian cancers. / Lin, Kedan; Rubinfeld, Bonnee; Zhang, Crystal; Firestein, Ron; Harstad, Eric; Roth, Leslie; Tsai, Siao Ping; Schutten, Melissa; Xu, Keyang; Hristopoulos, Maria; Polakis, Paul.

In: Clinical Cancer Research, Vol. 21, No. 22, 15.11.2015, p. 5139-5150.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Preclinical development of an anti-NaPi2b (SLC34A2) antibody-drug conjugate as a therapeutic for non-small cell lung and ovarian cancers

AU - Lin, Kedan

AU - Rubinfeld, Bonnee

AU - Zhang, Crystal

AU - Firestein, Ron

AU - Harstad, Eric

AU - Roth, Leslie

AU - Tsai, Siao Ping

AU - Schutten, Melissa

AU - Xu, Keyang

AU - Hristopoulos, Maria

AU - Polakis, Paul

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N2 - 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 crossreactive 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.

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