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Anti-tumor activity of stability-engineered IgG-like bispecific antibodies targeting TRAIL-R2 and LTβR

Jennifer S. Michaelson, Stephen J. Demarest, Brian Miller, Aldo Amatucci, William Snyder, Xiufeng Wu, Flora Huang, Samantha Phan, Sharon Gao, Adam Doern, Graham K. Farrington, Alexey Lugovskoy, Ingrid Joseph, Veronique Bailly, Xin Wang, Ellen Garber, Jeff Browning and Scott M. Glaser

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Bispecific antibodies (BsAbs) represent an emerging class of biologics that achieve dual targeting with a single agent. Recombinant DNA technologies have facilitated a variety of creative bispecific designs with many promising therapeutic applications; however, practical methods for producing high quality BsAbs that have good product stability, long serum half-life, straightforward purification, and scalable production have largely been limiting. Here we describe a protein-engineering approach for producing stable, scalable tetravalent IgG-like BsAbs. The stability-engineered IgG-like BsAb was envisioned to target and crosslink two TNF family member receptors, TRAIL-R2 (TNF-Related Apoptosis Inducing Ligand Receptor-2) and LTβR (Lymphotoxin-beta Receptor), expressed on the surface of epithelial tumor cells with the goal of triggering an enhanced anti-tumor effect. Our IgG-like BsAbs consists of a stability-engineered anti- LTβR single chain Fv (scFv) genetically fused to either the N- or C-terminus of the heavy chain of a full-length anti-TRAIL-R2 IgG1 monoclonal antibody. Both N- or C-terminal BsAbs were active in inhibiting tumor cell growth in vitro, and with some cell lines demonstrated enhanced activity relative to the combination of parental Abs.  Pharmacokinetic studies in mice revealed long serum half-lives for the BsAbs. In murine tumor xenograft models, therapeutic treatment with the BsAbs resulted in reduction in tumor volume either comparable to or greater than the combination of parental antibodies, indicating that simultaneously targeting and cross-linking receptor pairs is an effective strategy for treating tumor cells. These studies support that stability-engineering is an enabling step for producing scalable IgG-like BsAbs with properties desirable for biopharmaceutical development.

Authors

Jennifer S. Michaelson Corresponding author: jennifer.michaelson@biogenidec.com

Biogen Idec, Inc.

Stephen J. Demarest

Biogen Idec, Inc.

Brian Miller

Biogen Idec, Inc.

Aldo Amatucci

Biogen Idec, Inc.

William Snyder

Biogen Idec, Inc.

Xiufeng Wu

Biogen Idec, Inc.

Flora Huang

Biogen Idec, Inc.

Samantha Phan

Biogen Idec, Inc.

Sharon Gao

Biogen Idec, Inc.

Adam Doern

Biogen Idec, Inc.

Graham K. Farrington

Biogen Idec, Inc.

Alexey Lugovskoy

Biogen Idec, Inc.

Ingrid Joseph

Biogen Idec, Inc.

Veronique Bailly

Biogen Idec, Inc.

Xin Wang

AstraZeneca R&D

Ellen Garber

Biogen Idec, Inc.

Jeff Browning

Biogen Idec, Inc.

Scott M. Glaser Corresponding author: scott.glaser@biogenidec.com

Biogen Idec, Inc.

This is an open-access article

 Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.