eNews February 18, 2010

FcRn-'humanized' mice facilitate therapeutic antibody development

JAX professor constructs humanized mice to facilitate efficacy testing

Monoclonal therapeutic antibodies are well-recognized and useful treatments for many diseases, especially cancer and autoimmune disorders. A major reason for their usefulness is their improved pharmacokinetics, specifically their persistence in circulation and distribution to extravascular sites. The amount of time that they remain active in the body (technically, their serum half-life) depends on the strength of their affinity to the neonatal Fc receptor or Fc receptor, IgG, alpha chain transporter (FCGRT, formerly FcRn): the stronger their affinity, the longer their half-life.

In 2010, a team of researchers composed of scientists from Xencor, Inc. of Monrovia, California, and Professor Derry Roopenian of The Jackson Laboratory increased the efficacy of cancer therapeutic antibodies in humanized mice by engineering longer half-life variants of bevacizumab (Avastin), a humanized anti-vascular endothelial growth factor (VEGF) IgG1 antibody used to treat colorectal, lung, breast and renal cancers (Zalevsky et al. 2010).

Because FCGRTs are species-specific, the serum half-life of therapeutic antibodies designed to treat human diseases cannot be evaluated in normal mice. To circumvent this problem, Professor Roopenian constructed two "humanized" mice (Roopenian et al. 2003; Petkova et al. 2006). Both are deficient for mouse Fcgrt but are transgenic for human FCGRT (hFCRN). One of them is Rag1-deficient (produced by backcrossing to a Rag1-deficient mouse), rendering it immunodeficient and thus able to engraft and grow human tumors. The Fc-engineered Avastin variants were administered to the hFCRN-humanized mice and found to have from a three- to 20-fold greater affinity for hFCRN. To test the anti-tumor efficacy of the Avastin variants, the team administered them to immunodeficient hFCRN-humanized mice that had been engrafted with human tumors and found that they had significantly enhanced tumor-suppressing activity.

The results of this study strongly suggest that therapeutic antibodies engineered to interact more efficiently with FCRN can be administered less often, at smaller doses, and by different routes, making them more effective, flexible and convenient disease therapies. They also demonstrate the utility of FCRN-humanized mouse models for developing and evaluating preclinical therapeutic antibodies.

References

(Author in bold is a Jackson Laboratory scientist.)

Petkova SB, Akilesh S, Sproule TJ, Christianson GJ, Al Khabbaz H, Brown AC, Presta LG, Meng YG, Roopenian DC. 2006. Enhanced half-life of genetically engineered human IgG1 antibodies in a humanized FcRn mouse model: potential application in humorally mediated autoimmune disease. Int Immunol 18:1759-69.

Roopenian DC, Christianson GJ, Sproule TJ, Brown AC, Akilesh S, Jung N, Petkova S, Avanessian L, Choi EY, Shaffer DJ, Eden PA, Anderson CL. 2003. The MHC class I-like IgG receptor controls perinatal IgG transport, IgG homeostasis, and fate of IgG-Fc-coupled drugs. J Immunol 170:3528-33.