TY - JOUR
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
Y1 - 2018
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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85046761049&origin=inward
U2 - https://doi.org/10.1158/1535-7163.MCT-17-0813
DO - https://doi.org/10.1158/1535-7163.MCT-17-0813
M3 - Article
C2 - 29282299
SN - 1535-7163
VL - 17
SP - 638
EP - 649
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 3
ER -