Why is Pfizer interested in TPBG Gene Replacement?

What is TPBG?

Trophoblast glycoprotein (TPBG) is an oncofetal integral plasma membrane protein found in higher levels in embryonic development than healthy adults. The extracellular domain assists in cell adhesion and epithelial-mesenchymal transition, both occuring in early development and tumor growth.

How is TPBG currently being treated?

TPBG is the drug target of several anti-cancer drugs in pre-clinical development because it is highly expressed in cancer cells and not in healthy tissue.

MVA-5T4 or TroVax (Oxford Biomedica) is a modified vaccinia virus that expresses TPBG/5T4.

ABR-217620 or Anyara (Active Biotech) is a superantigen fused to an antibody.

PF-06263507 or AlmcMMAF (used in this study) is an antibody-drug conjugate of auristatin (microtubule-disrupting) fused to an antibody.

What was the aim of this article?

This work was attempting to knockin a human TPBG gene into mice to create a functional model that could be used to test TPBG drugs. In this case, the clinical-stage antibody-drug conjugate a1mcMMAF was tested. This model could provide more precise pharmacokinetic and pharmacodynamic studies of TPBG therapies.

What was the design of the experiment?

C57Bl/6 mice had the entire mouse coding sequence replaced with a human TPBG coding sequence using recombineering technology. Tissue samples were phenotyped then immunostained for TPBG levels. Pharmacokinetic studies were performed with A1mcMMAF on hTPBG-KI and wild type mice.

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