TY - JOUR
T1 - The melanosomal protein PMEL17 as a target for antibody drug conjugate therapy in melanoma
AU - Chen, Youjun
AU - Chalouni, Cecile
AU - Tan, Christine
AU - Clark, Robyn
AU - Venook, Rayna
AU - Ohri, Rachana
AU - Raab, Helga
AU - Firestein, Ron
AU - Mallet, William
AU - Polakis, Paul
PY - 2012/7/13
Y1 - 2012/7/13
N2 - Melanocytes uniquely express specialized genes required for pigment formation, some of which are maintained following their transformation to melanoma. Here we exploit this property to selectively target melanoma with an antibody drug conjugate (ADC) specific to PMEL17, the product of the SILV pigment- forming gene. We describe new PMEL17 antibodies that detect the endogenous protein. These antibodies help define the secretory fate of PMEL17 and demonstrate its utility as an ADC target. Although newly synthesized PMEL17 is ultimately routed to the melanosome, we find substantial amounts accessible to our antibodies at the cell surface that undergo internalization and routing to a LAMP1-enriched, lysosome-related organelle. Accordingly, an ADC reactive with PMEL17 exhibits target-dependent tumor cell killing in vitro and in vivo.
AB - Melanocytes uniquely express specialized genes required for pigment formation, some of which are maintained following their transformation to melanoma. Here we exploit this property to selectively target melanoma with an antibody drug conjugate (ADC) specific to PMEL17, the product of the SILV pigment- forming gene. We describe new PMEL17 antibodies that detect the endogenous protein. These antibodies help define the secretory fate of PMEL17 and demonstrate its utility as an ADC target. Although newly synthesized PMEL17 is ultimately routed to the melanosome, we find substantial amounts accessible to our antibodies at the cell surface that undergo internalization and routing to a LAMP1-enriched, lysosome-related organelle. Accordingly, an ADC reactive with PMEL17 exhibits target-dependent tumor cell killing in vitro and in vivo.
UR - http://www.scopus.com/inward/record.url?scp=84863788706&partnerID=8YFLogxK
U2 - 10.1074/jbc.M112.361485
DO - 10.1074/jbc.M112.361485
M3 - Article
C2 - 22613716
AN - SCOPUS:84863788706
SN - 0021-9258
VL - 287
SP - 24082
EP - 24091
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 29
ER -