An anti-gdnf family receptor alpha 1 (gfra1 antibody–drug conjugate for the treatment of hormone receptor–positive breast cancer

Sunil Bhakta, Lisa M. Crocker, Yvonne Chen, Meredith Hazen, Melissa M. Schutten, Dongwei Li, Coenraad Kuijl, Rachana Ohri, Fiona Zhong, Kirsten A. Poon, Mary Ann T. Go, Eric Cheng, Robert Piskol, Ron Firestein, Aimee Fourie-O'Donohue, Katherine R. Kozak, Helga Raab, Jo Anne Hongo, Deepak Sampath, Mark S. Dennis & 3 others Richard H. Scheller, Paul Polakis, Jagath R. Junutula

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Luminal A (hormone receptor-positive) breast cancer constitutes 70% of total breast cancer patients. In an attempt to develop a targeted therapeutic for this cancer indication, we have identified and characterized Glial cell line–Derived Neurotrophic Factor (GDNF) Family Receptor Alpha 1 (GFRA1) antibody–drug conjugates (ADC) using a cleavable valine-citrulline-MMAE (vcMMAE) linker-payload. RNAseq and IHC analysis confirmed the abundant expression of GFRA1 in luminal A breast cancer tissues, whereas minimal or no expression was observed in most normal tissues. Anti–GFRA-vcMMAE ADC internalized to the lysosomes and exhibited target-dependent killing of GFRA1-expressing cells both in vitro and in vivo. The ADCs using humanized anti-GFRA1 antibodies displayed robust therapeutic activity in clinically relevant cell line–derived (MCF7 and KPL-1) tumor xenograft models. The lead anti-GFRA1 ADC cross-reacts with rodent and cynomolgus monkey GFRA1 antigen and showed optimal pharmacokinetic properties in both species. These properties subsequently enabled a target-dependent toxicity study in rats. Anti-GFRA1 ADC is well tolerated in rats, as seen with other vcMMAE linker–payload based ADCs. Overall, these data suggest that anti–GFRA1-vcMMAE ADC may provide a targeted therapeutic opportunity for luminal A breast cancer patients. Mol Cancer Ther; 17(3); 638–49. 2017 AACR.

Original languageEnglish
Pages (from-to)638-649
Number of pages12
JournalMolecular Cancer Therapeutics
Volume17
Issue number3
DOIs
Publication statusPublished - 1 Mar 2018

Cite this

Bhakta, Sunil ; Crocker, Lisa M. ; Chen, Yvonne ; Hazen, Meredith ; Schutten, Melissa M. ; Li, Dongwei ; Kuijl, Coenraad ; Ohri, Rachana ; Zhong, Fiona ; Poon, Kirsten A. ; Go, Mary Ann T. ; Cheng, Eric ; Piskol, Robert ; Firestein, Ron ; Fourie-O'Donohue, Aimee ; Kozak, Katherine R. ; Raab, Helga ; Hongo, Jo Anne ; Sampath, Deepak ; Dennis, Mark S. ; Scheller, Richard H. ; Polakis, Paul ; Junutula, Jagath R. / An anti-gdnf family receptor alpha 1 (gfra1 antibody–drug conjugate for the treatment of hormone receptor–positive breast cancer. In: Molecular Cancer Therapeutics. 2018 ; Vol. 17, No. 3. pp. 638-649.
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title = "An anti-gdnf family receptor alpha 1 (gfra1 antibody–drug conjugate for the treatment of hormone receptor–positive breast cancer",
abstract = "Luminal A (hormone receptor-positive) breast cancer constitutes 70{\%} of total breast cancer patients. In an attempt to develop a targeted therapeutic for this cancer indication, we have identified and characterized Glial cell line–Derived Neurotrophic Factor (GDNF) Family Receptor Alpha 1 (GFRA1) antibody–drug conjugates (ADC) using a cleavable valine-citrulline-MMAE (vcMMAE) linker-payload. RNAseq and IHC analysis confirmed the abundant expression of GFRA1 in luminal A breast cancer tissues, whereas minimal or no expression was observed in most normal tissues. Anti–GFRA-vcMMAE ADC internalized to the lysosomes and exhibited target-dependent killing of GFRA1-expressing cells both in vitro and in vivo. The ADCs using humanized anti-GFRA1 antibodies displayed robust therapeutic activity in clinically relevant cell line–derived (MCF7 and KPL-1) tumor xenograft models. The lead anti-GFRA1 ADC cross-reacts with rodent and cynomolgus monkey GFRA1 antigen and showed optimal pharmacokinetic properties in both species. These properties subsequently enabled a target-dependent toxicity study in rats. Anti-GFRA1 ADC is well tolerated in rats, as seen with other vcMMAE linker–payload based ADCs. Overall, these data suggest that anti–GFRA1-vcMMAE ADC may provide a targeted therapeutic opportunity for luminal A breast cancer patients. Mol Cancer Ther; 17(3); 638–49. 2017 AACR.",
author = "Sunil Bhakta and Crocker, {Lisa M.} and Yvonne Chen and Meredith Hazen and Schutten, {Melissa M.} and Dongwei Li and Coenraad Kuijl and Rachana Ohri and Fiona Zhong and Poon, {Kirsten A.} and Go, {Mary Ann T.} and Eric Cheng and Robert Piskol and Ron Firestein and Aimee Fourie-O'Donohue and Kozak, {Katherine R.} and Helga Raab and Hongo, {Jo Anne} and Deepak Sampath and Dennis, {Mark S.} and Scheller, {Richard H.} and Paul Polakis and Junutula, {Jagath R.}",
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Bhakta, S, Crocker, LM, Chen, Y, Hazen, M, Schutten, MM, Li, D, Kuijl, C, Ohri, R, Zhong, F, Poon, KA, Go, MAT, Cheng, E, Piskol, R, Firestein, R, Fourie-O'Donohue, A, Kozak, KR, Raab, H, Hongo, JA, Sampath, D, Dennis, MS, Scheller, RH, Polakis, P & Junutula, JR 2018, 'An anti-gdnf family receptor alpha 1 (gfra1 antibody–drug conjugate for the treatment of hormone receptor–positive breast cancer' Molecular Cancer Therapeutics, vol. 17, no. 3, pp. 638-649. https://doi.org/10.1158/1535-7163.MCT-17-0813

An anti-gdnf family receptor alpha 1 (gfra1 antibody–drug conjugate for the treatment of hormone receptor–positive breast cancer. / Bhakta, Sunil; Crocker, Lisa M.; Chen, Yvonne; Hazen, Meredith; Schutten, Melissa M.; Li, Dongwei; Kuijl, Coenraad; Ohri, Rachana; Zhong, Fiona; Poon, Kirsten A.; Go, Mary Ann T.; Cheng, Eric; Piskol, Robert; Firestein, Ron; Fourie-O'Donohue, Aimee; Kozak, Katherine R.; Raab, Helga; Hongo, Jo Anne; Sampath, Deepak; Dennis, Mark S.; Scheller, Richard H.; Polakis, Paul; Junutula, Jagath R.

In: Molecular Cancer Therapeutics, Vol. 17, No. 3, 01.03.2018, p. 638-649.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - An anti-gdnf family receptor alpha 1 (gfra1 antibody–drug conjugate for the treatment of hormone receptor–positive breast cancer

AU - Bhakta, Sunil

AU - Crocker, Lisa M.

AU - Chen, Yvonne

AU - Hazen, Meredith

AU - Schutten, Melissa M.

AU - Li, Dongwei

AU - Kuijl, Coenraad

AU - Ohri, Rachana

AU - Zhong, Fiona

AU - Poon, Kirsten A.

AU - Go, Mary Ann T.

AU - Cheng, Eric

AU - Piskol, Robert

AU - Firestein, Ron

AU - Fourie-O'Donohue, Aimee

AU - Kozak, Katherine R.

AU - Raab, Helga

AU - Hongo, Jo Anne

AU - Sampath, Deepak

AU - Dennis, Mark S.

AU - Scheller, Richard H.

AU - Polakis, Paul

AU - Junutula, Jagath R.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - Luminal A (hormone receptor-positive) breast cancer constitutes 70% of total breast cancer patients. In an attempt to develop a targeted therapeutic for this cancer indication, we have identified and characterized Glial cell line–Derived Neurotrophic Factor (GDNF) Family Receptor Alpha 1 (GFRA1) antibody–drug conjugates (ADC) using a cleavable valine-citrulline-MMAE (vcMMAE) linker-payload. RNAseq and IHC analysis confirmed the abundant expression of GFRA1 in luminal A breast cancer tissues, whereas minimal or no expression was observed in most normal tissues. Anti–GFRA-vcMMAE ADC internalized to the lysosomes and exhibited target-dependent killing of GFRA1-expressing cells both in vitro and in vivo. The ADCs using humanized anti-GFRA1 antibodies displayed robust therapeutic activity in clinically relevant cell line–derived (MCF7 and KPL-1) tumor xenograft models. The lead anti-GFRA1 ADC cross-reacts with rodent and cynomolgus monkey GFRA1 antigen and showed optimal pharmacokinetic properties in both species. These properties subsequently enabled a target-dependent toxicity study in rats. Anti-GFRA1 ADC is well tolerated in rats, as seen with other vcMMAE linker–payload based ADCs. Overall, these data suggest that anti–GFRA1-vcMMAE ADC may provide a targeted therapeutic opportunity for luminal A breast cancer patients. Mol Cancer Ther; 17(3); 638–49. 2017 AACR.

AB - Luminal A (hormone receptor-positive) breast cancer constitutes 70% of total breast cancer patients. In an attempt to develop a targeted therapeutic for this cancer indication, we have identified and characterized Glial cell line–Derived Neurotrophic Factor (GDNF) Family Receptor Alpha 1 (GFRA1) antibody–drug conjugates (ADC) using a cleavable valine-citrulline-MMAE (vcMMAE) linker-payload. RNAseq and IHC analysis confirmed the abundant expression of GFRA1 in luminal A breast cancer tissues, whereas minimal or no expression was observed in most normal tissues. Anti–GFRA-vcMMAE ADC internalized to the lysosomes and exhibited target-dependent killing of GFRA1-expressing cells both in vitro and in vivo. The ADCs using humanized anti-GFRA1 antibodies displayed robust therapeutic activity in clinically relevant cell line–derived (MCF7 and KPL-1) tumor xenograft models. The lead anti-GFRA1 ADC cross-reacts with rodent and cynomolgus monkey GFRA1 antigen and showed optimal pharmacokinetic properties in both species. These properties subsequently enabled a target-dependent toxicity study in rats. Anti-GFRA1 ADC is well tolerated in rats, as seen with other vcMMAE linker–payload based ADCs. Overall, these data suggest that anti–GFRA1-vcMMAE ADC may provide a targeted therapeutic opportunity for luminal A breast cancer patients. Mol Cancer Ther; 17(3); 638–49. 2017 AACR.

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U2 - 10.1158/1535-7163.MCT-17-0813

DO - 10.1158/1535-7163.MCT-17-0813

M3 - Article

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JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

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