A two-in-one antibody against HER3 and EGFR has superior inhibitory activity compared with monospecific antibodies.
Extensive crosstalk among ErbB/HER receptors suggests that blocking signaling from more than one family member may be essential to effectively treat cancer and limit drug resistance. We generated a conventional IgG molecule MEHD7945A with dual HER3/EGFR specificity by phage display engineering and used structural and mutational studies to understand how a single antigen recognition surface binds two epitopes with high affinity. As a human IgG1, MEHD7945A exhibited dual action by inhibiting EGFR- and HER3-mediated signaling in vitro and in vivo and the ability to engage immune effector functions. Compared with monospecific anti-HER antibodies, MEHD7945A was more broadly efficacious in multiple tumor models, showing that combined inhibition of EGFR and HER3 with a single antibody is beneficial.
Department of Research Oncology, Genentech, Inc, South San Francisco, CA 94080, USA.
Gabriele
G
Schaefer
Lauric
L
Haber
Lisa M
LM
Crocker
Steven
S
Shia
Lily
L
Shao
Donald
D
Dowbenko
Klara
K
Totpal
Anne
A
Wong
Chingwei V
CV
Lee
Scott
S
Stawicki
Robyn
R
Clark
Carter
C
Fields
Gail D
GD
Lewis Phillips
Rodney A
RA
Prell
Dimitry M
DM
Danilenko
Yvonne
Y
Franke
Jean-Philippe
JP
Stephan
Jiyoung
J
Hwang
Yan
Y
Wu
Jenny
J
Bostrom
Mark X
MX
Sliwkowski
Germaine
G
Fuh
Charles
C
Eigenbrot
D000818:Animals; D018033:Antibodies, Bispecific / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000918:Antibody Specificity; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D001666:Binding Sites, Antibody; D001667:Binding, Competitive; D000068818:Cetuximab; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D020935:MAP Kinase Signaling System; D008252:Macaca fascicularis; D051379:Mice; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology; D015398:Signal Transduction
D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007074:Immunoglobulin G; C569960:MEHD7945A; C512478:EGFR protein, human; D066246:ErbB Receptors; D020893:Receptor, ErbB-3; D051057:Proto-Oncogene Proteins c-akt; D000068818:Cetuximab