Stable IgG-like bispecific antibodies directed toward the type I insulin-like growth factor receptor demonstrate enhanced ligand blockade and anti-tumor activity.
Bispecific antibodies (BsAbs) target multiple epitopes on the same molecular target or different targets. Although interest in BsAbs has persisted for decades, production of stable and active BsAbs has hindered their clinical evaluation. Here, we describe the production and characterization of tetravalent IgG-like BsAbs that combine the activities of allosteric and competitive inhibitors of the type-I insulin-like growth factor receptor (IGF-1R). The BsAbs, which were engineered for thermal stability, express well, demonstrate favorable biophysical properties, and recognize both epitopes on IGF-1R. Only one BsAb with a unique geometry, denoted BIIB4-5scFv, was capable of engaging all four of its binding arms simultaneously. All the BsAbs (especially BIIB4-5scFv) demonstrated enhanced ligand blocking over the single monoclonal antibodies (mAbs), particularly at high ligand concentrations. The pharmacokinetic profiles of two IgG-like BsAbs were tested in nude mice and shown to be comparable with that of the parental mAbs. The BsAbs, especially BIIB4-5scFv, demonstrated an improved ability to reduce the growth of multiple tumor cell lines and to inhibit ligand-induced IGF-1R signaling in tumor cells over the parental mAbs. BIIB4-5scFv also led to superior tumor growth inhibition over its parental mAbs in vivo. In summary, BsAbs that bridge multiple inhibitory mechanisms against a single target may generally represent a more effective strategy for intervention in oncology or other indications compared with traditional mAb therapy.
Biogen Idec, San Diego, California 92122, USA. jianying_dong@yahoo.com
Jianying
J
Dong
Arlene
A
Sereno
William B
WB
Snyder
Brian R
BR
Miller
Susan
S
Tamraz
Adam
A
Doern
Michael
M
Favis
Xiufeng
X
Wu
Hon
H
Tran
Emma
E
Langley
Ingrid
I
Joseph
Antonio
A
Boccia
Rebecca
R
Kelly
Kathleen
K
Wortham
Qin
Q
Wang
Lisa
L
Berquist
Flora
F
Huang
Sharon X
SX
Gao
Ying
Y
Zhang
Alexey
A
Lugovskoy
Shelly
S
Martin
Heather
H
Gouvis
Steven
S
Berkowitz
Gisela
G
Chiang
Mitchell
M
Reff
Scott M
SM
Glaser
Kandasamy
K
Hariharan
Stephen J
SJ
Demarest
D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000493:pharmacokinetics* / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived / Q000276:immunology / Q000493:pharmacokinetics* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000276:immunology / Q000493:pharmacokinetics* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004355:Drug Stability; D006801:Humans; D007074:Immunoglobulin G; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology; D055550:Protein Stability; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D018033:Antibodies, Bispecific; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D007074:Immunoglobulin G; D008024:Ligands; D017526:Receptor, IGF Type 1