A New Tri-Fab Bispecific Antibody for Pretargeting Trop-2–Expressing Epithelial Cancers

Journal of Nuclear Medicine

Chien-Hsing Chang¹  William J. McBride¹  David M. Goldenberg¹  Catharina M. van Rij¹  Celeste Regino¹  Cathelijne Frielink¹  Thomas M. Cardillo¹  Edmund A. Rossi¹  Habibe Karacay¹  Otto C. Boerman¹  Robert M. Sharkey¹ 

关键词: bispecific antibody;    epithelial cancers;    epithelial glycoprotein-1 (EGP-1);    pretargeting;    radioimmunodetection;    Trop-2;   

DOI  :  10.2967/jnumed.112.104364

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

RS7 is an internalizing anti-Trop-2 pancarcinoma antibody capable of targeting most epithelial cancers. Because pretargeting strategies could improve the tumor localization of radionuclides, a new anti-Trop-2 × antihapten bispecific antibody for pretargeting, based on humanized RS7, was prepared and evaluated with a radiolabeled hapten-peptide in vitro and in vivo to determine whether its internalization properties would interfere with pretargeting. Methods: The anti-Trop-2 × antihapten bispecific antibody, TF12, was prepared using the modular dock-and-lock method. TF12 and humanized RS7 binding was assessed by cell binding assays and fluorescence-activated cell sorting analysis in a variety of human carcinoma cell lines. The internalization of TF12 was evaluated in vitro using a fluorescent TF12 conjugate or hapten-peptide and 111In-labeled TF12 and RS7. The biodistribution of TF12 and its use as a pretargeting agent with an 111In-labeled hapten-peptide were assessed in several human epithelial cancer xenografts. Dose optimization was examined in 2 tumor models. Results: TF12 internalizes, but a substantial fraction remained accessible on the tumor surface. Fluorescence-activated cell sorting analysis showed only a minor change in fluorescent signal when the tumor was probed with a fluorescent hapten-peptide over 4 h, and microscopy showed substantial membrane staining when reassessed at 24 h after TF12 exposure. Only 40.1% of 111In-TF12 was internalized after 24 h. In vivo, excellent tumor localization of the 111In-labeled peptide was observed in several tumor models. Conclusion: TF12 was retained sufficiently on the cell surface in several epithelial cancers, thereby making it suitable for pretargeted imaging and therapy of various Trop-2–expressing carcinomas.

【 授权许可】

Unknown