Structure-based humanization of therapeutic antibodies

BIOT 433

Karl Hanf, karlhanf@comcast.net1, You Li2, Kenneth Simon2, Ling Ling Chen1, Matthew Jarpe3, Ellen Garber1, Fred Taylor2, Laura Silvian, laura.silvian@biogenidec.com1, Joseph Arndt, joseph.arndt@biogenidec.com1, and Alexey Lugovskoy, alexey.lugovskoy@biogenidec.com1. (1) Drug Discovery, Biogen Idec Inc, 14 Cambridge Center, Cambridge, MA 02142, (2) Molecular Engineering, Biogen Idec Inc, 14 Cambridge Center, Cambridge, MA 02142, (3) Physical Biochemistry, Biogen Idec Inc, 14 Cambridge Center, Cambridge, MA 02142
Antibodies are well-established protein therapeutic agents. Typically, high-affinity antibodies are obtained by immunization of rodent species and need to be humanized to reduce their immunogenicity, which could otherwise lead to adverse reactions in patients or inferior pharmacokinetic behavior. We have developed a novel structure-based method of antibody humanization through remodeling of complementarity-determining regions (CDRs). Poor interactions between mature murine CDRs and the chosen human framework are resolved by changing the back side of murine CDRs to fit the human framework, which results in excellent retention of binding to antigen. Further, we redesigned antibodies for improved stability and affinity using structure-based computational optimization with dead-end elimination followed by Poisson-Boltzmann electrostatics.
 

Biophysical and Biomolecular Symposium: Protein Engineering
8:00 AM-11:00 AM, Thursday, August 23, 2007 BCEC -- 108, Oral

Division of Biochemical Technology

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007