Oxford BioMedica PLC (OXBDF)

[georgejjl]

5T4 ADC at Medimmune

Preclinical evaluation of MEDI0641, a pyrrolobenzodiazepine-conjugated antibody-drug conjugate targeting 5T4.

Harper J1, Lloyd C2, Dimasi N3, Toader D3, Marwood R2, Lewis L2, Bannister D4, Jovanovic J2, Fleming R3, d'Hooge F5, Mao S6, Marrero AM6, Korade M6, Strout P6, Xu L3, Chen C6, Wetzel L6, Breen S6, van Vlerken-Ysla L6, Jalla S7, Rebelatto M8, Zhong H6, Hurt EM6, Hinrichs MJ9, Huang K6, Howard PW5, Tice DA6, Hollingsworth RE6, Herbst R6, Kamal A10.
Author information
1
Oncology Research, MedImmune, LLC [e-mail].
2
Antibody Discovery and Protein Engineering, MedImmune, Ltd.
3
Antibody Discovery and Protein Engineering, MedImmune, LLC.
4
Antibody Discovery and Protein Engineering, MedImmune Ltd.
5
Spirogen.
6
Oncology Research, MedImmune, LLC.
7
Project Management, MedImmune, LLC.
8
Pathology, MedImmune, LLC.
9
Biologics Safety Assessment, MedImmune, LLC.
10
Ferring Pharmaceuticals.
Abstract
Antibody-drug conjugates (ADCs) are used to selectively deliver cytotoxic agents to tumors and have the potential for increased clinical benefit to cancer patients. 5T4 is an oncofetal antigen overexpressed on the cell surface in many carcinomas on both bulk tumor cells as well as cancer stem cells (CSCs), has very limited normal tissue expression, and can internalize when bound by an antibody. An anti-5T4 antibody was identified and optimized for efficient binding and internalization in a target-specific manner, and engineered cysteines were incorporated into the molecule for site-specific conjugation. ADCs targeting 5T4 were constructed by site-specifically conjugating the antibody with payloads that possess different mechanisms of action, either a DNA cross-linking pyrrolobenzodiazepine (PBD) dimer or a microtubule-destabilizing tubulysin, so that each ADC had a drug:antibody ratio of 2. The resulting ADCs demonstrated significant target-dependent activity in vitro and in vivo, however the ADC conjugated with a PBD payload (5T4-PBD) elicited more durable anti-tumor responses in vivo than the tubulysin conjugate in xenograft models. Likewise, the 5T4-PBD more potently inhibited the growth of 5T4-positive CSCs in vivo, which likely contributed to its superior anti-tumor activity. Given that the 5T4-PBD possessed both potent anti-tumor activity as well as anti-CSC activity, and thus could potentially target bulk tumor cells and CSCs in target-positive indications, it was further evaluated in non-GLP rat toxicology studies that demonstrated excellent in vivo stability with an acceptable safety profile. Taken together, these preclinical data support further development of 5T4-PBD, also known as MEDI0641, against 5T4+ cancer indications.

https://www.ncbi.nlm.nih.gov/pubmed/28522587

Good luck and GOD bless,

George