title: A bi-functional antibody-receptor domain fusion protein simultaneously targeting IGF-IR and VEGF for degradation.
abstract: Bi-specific antibodies (BsAbs), which can simultaneously block 2 tumor targets, have emerged as promising therapeutic alternatives to combinations of individual monoclonal antibodies. Here, we describe the engineering and development of a novel, human bi-functional antibody-receptor domain fusion molecule with ligand capture (bi-AbCap) through the fusion of the domain 2 of human vascular endothelial growth factor receptor 1 (VEGFR1) to an antibody directed against insulin-like growth factor - type I receptor (IGF-IR). The bi-AbCap possesses excellent stability and developability, and is the result of minimal engineering. Beyond potent neutralizing activities against IGF-IR and VEGF, the bi-AbCap is capable of cross-linking VEGF to IGF-IR, leading to co-internalization and degradation of both targets by tumor cells. In multiple mouse xenograft tumor models, the bi-AbCap improves anti-tumor activity over individual monotherapies. More importantly, it exhibits superior inhibition of tumor growth, compared with the combination of anti-IGF-IR and anti-VEGF therapies, via powerful blockade of both direct tumor cell growth and tumor angiogenesis. The unique "capture-for-degradation" mechanism of the bi-AbCap is informative for the design of next-generation bi-functional anti-cancer therapies directed against independent signaling pathways. The bi-AbCap design represents an alternative approach to the creation of dual-targeting antibody fusion molecules by taking advantage of natural receptor-ligand interactions.
authors.affiliation: a Antibody Technology; Eli Lilly and Company ; New York , NY USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shen
authors.forename: Lin
authors.initials: L
authors.lastname: Zeng
authors.forename: Ruslan
authors.initials: R
authors.lastname: Novosyadlyy
authors.forename: Amelie
authors.initials: A
authors.lastname: Forest
authors.forename: Aiping
authors.initials: A
authors.lastname: Zhu
authors.forename: Andrew
authors.initials: A
authors.lastname: Korytko
authors.forename: Haifan
authors.initials: H
authors.lastname: Zhang
authors.forename: Scott W
authors.initials: SW
authors.lastname: Eastman
authors.forename: Michael
authors.initials: M
authors.lastname: Topper
authors.forename: Sagit
authors.initials: S
authors.lastname: Hindi
authors.forename: Nicole
authors.initials: N
authors.lastname: Covino
authors.forename: Kris
authors.initials: K
authors.lastname: Persaud
authors.forename: Yun
authors.initials: Y
authors.lastname: Kang
authors.forename: Douglas
authors.initials: D
authors.lastname: Burtrum
authors.forename: David
authors.initials: D
authors.lastname: Surguladze
authors.forename: Marie
authors.initials: M
authors.lastname: Prewett
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Chintharlapalli
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Wroblewski
authors.forename: Juqun
authors.initials: J
authors.lastname: Shen
authors.forename: Paul
authors.initials: P
authors.lastname: Balderes
authors.forename: Zhenping
authors.initials: Z
authors.lastname: Zhu
authors.forename: Marshall
authors.initials: M
authors.lastname: Snavely
authors.forename: Dale L
authors.initials: DL
authors.lastname: Ludwig
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D000915:Antibody Affinity; D002851:Chromatography, High Pressure Liquid; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009374:Neoplasms, Experimental / Q000188:drug therapy; D055550:Protein Stability; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D020349:Surface Plasmon Resonance; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; C000597236:IGF1R protein, human; D017451:Receptors, Somatomedin; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D017526:Receptor, IGF Type 1
keywords: IGF-IR; VEGF; VEGFR1; VEGFR2; angiogenesis; antibody fusion; bi-functional antibody; bispecific antibody; degradation; internalization