Novel Transgenic Mouse Models Addressing Outstanding Translational Barriers in Antibody-Based Therapeutics

ABSTRACT
Monoclonal antibodies have played a pivotal role in the diagnosis and treatment of cancer for nearly two decades
and continue to grow at an exponential pace. Initially developed for their exceptional ability to target tumor
antigens and elicit antibody-dependent cellular cytotoxicity (ADCC), they have more recently been used to
modulate a patient’s immune system for anti-cancer immunotherapy. While the generation and development of
antibodies targeting various cell surface proteins has rapidly progressed, appropriate model systems for pre-
clinical testing of such therapeutics has lagged. This is because human antibodies i) don’t fully engage murine
or non-human primate Fc receptors (FcγRs), ii) are foreign proteins that are rapidly rejected in allogeneic hosts
and iii) are often inappropriately tested in immunodeficient xenograft models lacking adaptive immune cells or
homologous FcγR. Thus, our studies have focused on the generation and testing of clinically relevant models to
better understand the in vivo activity of diagnostic and therapeutic antibodies. The current proposal aims to now
generate and fully characterize novel murine models that allow better preclinical testing of human antibodies by
engineering our previously developed humanized FcγR mouse strains to express human FcRn and IgG1.
Expression of human FcRn will allow more accurate pharmacokinetic analysis of human antibodies and
assessment of methods aimed at generating antibodies with extended in vivo half-life. By replacing the mouse
heavy chain with the constant regions of human IgG1, this model will also allow chronic administration of human
IgG-based therapeutics without developing anti-drug antibody responses. By addressing two major hurdles in
the field of antibody therapeutics, these models will allow more rapid and efficient pre-clinical toxicology testing
and potentially uncover novel mechanisms of Fc-engineered antibodies. Additionally, given the growing interest
in immunotherapy, having an immunocompetent model provides an additional advantage over current xenograft
models. Finally, as recent data suggest an important role for Fc-FcγR in radiolabeled antibody diagnostics, these
models will provide a clinically relevant model to help improve the development and testing of innovative
antibody-based molecules for the in vivo detection and localization of neoplasms.

Grant Number: 5R01CA244327-05
NIH Institute/Center: NIH
Principal Investigator: Stylianos Bournazos