An antibody-drug conjugate directed against lymphocyte antigen 6 complex, locus E (LY6E) provides robust tumor killing in a wide range of solid tumor malignancies

Jyoti Asundi, Lisa Crocker, Jarrod Tremayne, Peter Chang, Chie Sakanaka, Josh Tanguay, Susan Spencer, Sreedevi Chalasani, Elizabeth Luis, Karen Gascoigne, Rupal Desai, Rajiv Raja, Brad A. Friedman, Peter M. Haverty, Paul Polakis, Ron Firestein

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12 Citations (Scopus)

Abstract

Purpose: Chemotherapies are limited by a narrow therapeutic index resulting in suboptimal exposure of the tumor to the drug and acquired tumor resistance. One approach to overcome this is through antibody-drug conjugates (ADC) that facilitate greater potency via target-specific delivery of highly potent cytotoxic agents. Experimental Design: In this study, we used a bioinformatics approach to identify the lymphocyte antigen 6 complex locus E (LY6E), an IFN-inducible glycosylphosphatidylinositol (GPI)-linked cell membrane protein as a promising ADC target. We developed a monoclonal anti-LY6E antibody and characterized in situ LY6E expression in over 750 cancer specimens and normal tissues. Target-dependent anti-LY6E ADC killing was investigated both in vitro and in vivo using patient-derived xenograft models. Results: Using in silico approaches, we found that LY6E was significantly overexpressed and amplified in a wide array of different human solid tumors. IHC analysis revealed high LY6E protein expression in a number of tumor types, such as breast, lung, gastric, ovarian, pancreatic, kidney and head/neck carcinomas. Characterization of the endocytic pathways for LY6E revealed that the LY6E-specific antibody is internalized into cells leading to lysosomal accumulation. Consistent with this, a LY6E-specific ADC inhibited in vitro cell proliferation and produced durable tumor regression in vivo in clinically relevant LY6E-expressing xenograft models. Conclusions: Our results identify LY6E as a highly promising molecular ADC target for a variety of solid tumortypes with current unmet medical need.

Original languageEnglish
Pages (from-to)3252-3262
Number of pages11
JournalClinical Cancer Research
Volume21
Issue number14
DOIs
Publication statusPublished - 15 Jul 2015
Externally publishedYes

Cite this

Asundi, Jyoti ; Crocker, Lisa ; Tremayne, Jarrod ; Chang, Peter ; Sakanaka, Chie ; Tanguay, Josh ; Spencer, Susan ; Chalasani, Sreedevi ; Luis, Elizabeth ; Gascoigne, Karen ; Desai, Rupal ; Raja, Rajiv ; Friedman, Brad A. ; Haverty, Peter M. ; Polakis, Paul ; Firestein, Ron. / An antibody-drug conjugate directed against lymphocyte antigen 6 complex, locus E (LY6E) provides robust tumor killing in a wide range of solid tumor malignancies. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 14. pp. 3252-3262.
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title = "An antibody-drug conjugate directed against lymphocyte antigen 6 complex, locus E (LY6E) provides robust tumor killing in a wide range of solid tumor malignancies",
abstract = "Purpose: Chemotherapies are limited by a narrow therapeutic index resulting in suboptimal exposure of the tumor to the drug and acquired tumor resistance. One approach to overcome this is through antibody-drug conjugates (ADC) that facilitate greater potency via target-specific delivery of highly potent cytotoxic agents. Experimental Design: In this study, we used a bioinformatics approach to identify the lymphocyte antigen 6 complex locus E (LY6E), an IFN-inducible glycosylphosphatidylinositol (GPI)-linked cell membrane protein as a promising ADC target. We developed a monoclonal anti-LY6E antibody and characterized in situ LY6E expression in over 750 cancer specimens and normal tissues. Target-dependent anti-LY6E ADC killing was investigated both in vitro and in vivo using patient-derived xenograft models. Results: Using in silico approaches, we found that LY6E was significantly overexpressed and amplified in a wide array of different human solid tumors. IHC analysis revealed high LY6E protein expression in a number of tumor types, such as breast, lung, gastric, ovarian, pancreatic, kidney and head/neck carcinomas. Characterization of the endocytic pathways for LY6E revealed that the LY6E-specific antibody is internalized into cells leading to lysosomal accumulation. Consistent with this, a LY6E-specific ADC inhibited in vitro cell proliferation and produced durable tumor regression in vivo in clinically relevant LY6E-expressing xenograft models. Conclusions: Our results identify LY6E as a highly promising molecular ADC target for a variety of solid tumortypes with current unmet medical need.",
author = "Jyoti Asundi and Lisa Crocker and Jarrod Tremayne and Peter Chang and Chie Sakanaka and Josh Tanguay and Susan Spencer and Sreedevi Chalasani and Elizabeth Luis and Karen Gascoigne and Rupal Desai and Rajiv Raja and Friedman, {Brad A.} and Haverty, {Peter M.} and Paul Polakis and Ron Firestein",
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Asundi, J, Crocker, L, Tremayne, J, Chang, P, Sakanaka, C, Tanguay, J, Spencer, S, Chalasani, S, Luis, E, Gascoigne, K, Desai, R, Raja, R, Friedman, BA, Haverty, PM, Polakis, P & Firestein, R 2015, 'An antibody-drug conjugate directed against lymphocyte antigen 6 complex, locus E (LY6E) provides robust tumor killing in a wide range of solid tumor malignancies', Clinical Cancer Research, vol. 21, no. 14, pp. 3252-3262. https://doi.org/10.1158/1078-0432.CCR-15-0156

An antibody-drug conjugate directed against lymphocyte antigen 6 complex, locus E (LY6E) provides robust tumor killing in a wide range of solid tumor malignancies. / Asundi, Jyoti; Crocker, Lisa; Tremayne, Jarrod; Chang, Peter; Sakanaka, Chie; Tanguay, Josh; Spencer, Susan; Chalasani, Sreedevi; Luis, Elizabeth; Gascoigne, Karen; Desai, Rupal; Raja, Rajiv; Friedman, Brad A.; Haverty, Peter M.; Polakis, Paul; Firestein, Ron.

In: Clinical Cancer Research, Vol. 21, No. 14, 15.07.2015, p. 3252-3262.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - An antibody-drug conjugate directed against lymphocyte antigen 6 complex, locus E (LY6E) provides robust tumor killing in a wide range of solid tumor malignancies

AU - Asundi, Jyoti

AU - Crocker, Lisa

AU - Tremayne, Jarrod

AU - Chang, Peter

AU - Sakanaka, Chie

AU - Tanguay, Josh

AU - Spencer, Susan

AU - Chalasani, Sreedevi

AU - Luis, Elizabeth

AU - Gascoigne, Karen

AU - Desai, Rupal

AU - Raja, Rajiv

AU - Friedman, Brad A.

AU - Haverty, Peter M.

AU - Polakis, Paul

AU - Firestein, Ron

PY - 2015/7/15

Y1 - 2015/7/15

N2 - Purpose: Chemotherapies are limited by a narrow therapeutic index resulting in suboptimal exposure of the tumor to the drug and acquired tumor resistance. One approach to overcome this is through antibody-drug conjugates (ADC) that facilitate greater potency via target-specific delivery of highly potent cytotoxic agents. Experimental Design: In this study, we used a bioinformatics approach to identify the lymphocyte antigen 6 complex locus E (LY6E), an IFN-inducible glycosylphosphatidylinositol (GPI)-linked cell membrane protein as a promising ADC target. We developed a monoclonal anti-LY6E antibody and characterized in situ LY6E expression in over 750 cancer specimens and normal tissues. Target-dependent anti-LY6E ADC killing was investigated both in vitro and in vivo using patient-derived xenograft models. Results: Using in silico approaches, we found that LY6E was significantly overexpressed and amplified in a wide array of different human solid tumors. IHC analysis revealed high LY6E protein expression in a number of tumor types, such as breast, lung, gastric, ovarian, pancreatic, kidney and head/neck carcinomas. Characterization of the endocytic pathways for LY6E revealed that the LY6E-specific antibody is internalized into cells leading to lysosomal accumulation. Consistent with this, a LY6E-specific ADC inhibited in vitro cell proliferation and produced durable tumor regression in vivo in clinically relevant LY6E-expressing xenograft models. Conclusions: Our results identify LY6E as a highly promising molecular ADC target for a variety of solid tumortypes with current unmet medical need.

AB - Purpose: Chemotherapies are limited by a narrow therapeutic index resulting in suboptimal exposure of the tumor to the drug and acquired tumor resistance. One approach to overcome this is through antibody-drug conjugates (ADC) that facilitate greater potency via target-specific delivery of highly potent cytotoxic agents. Experimental Design: In this study, we used a bioinformatics approach to identify the lymphocyte antigen 6 complex locus E (LY6E), an IFN-inducible glycosylphosphatidylinositol (GPI)-linked cell membrane protein as a promising ADC target. We developed a monoclonal anti-LY6E antibody and characterized in situ LY6E expression in over 750 cancer specimens and normal tissues. Target-dependent anti-LY6E ADC killing was investigated both in vitro and in vivo using patient-derived xenograft models. Results: Using in silico approaches, we found that LY6E was significantly overexpressed and amplified in a wide array of different human solid tumors. IHC analysis revealed high LY6E protein expression in a number of tumor types, such as breast, lung, gastric, ovarian, pancreatic, kidney and head/neck carcinomas. Characterization of the endocytic pathways for LY6E revealed that the LY6E-specific antibody is internalized into cells leading to lysosomal accumulation. Consistent with this, a LY6E-specific ADC inhibited in vitro cell proliferation and produced durable tumor regression in vivo in clinically relevant LY6E-expressing xenograft models. Conclusions: Our results identify LY6E as a highly promising molecular ADC target for a variety of solid tumortypes with current unmet medical need.

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