Design, construction, and in vitro analyses of multivalent antibodies.
Some Abs are more efficacious after being cross-linked to form dimers or multimers, presumably as a result of binding to and clustering more surface target to either amplify or diversify cellular signaling. To improve the therapeutic potency of these types of Abs, we designed and generated Abs that express tandem Fab repeats with the aim of mimicking cross-linked Abs. The versatile design of the system enables the creation of a series of multivalent human IgG Ab forms including tetravalent IgG1, tetravalent F(ab')2, and linear Fab multimers with either three or four consecutively linked Fabs. The multimerized Abs target the cell surface receptors HER2, death receptor 5, and CD20, and are more efficacious than their parent mAbs in triggering antitumor cellular responses, indicating they could be useful both as reagents for study as well as novel therapeutics.
Miller
Kathy
K
Department of Immunology, Genentech, Inc., South San Francisco, CA 94080, USA. kathy.miller6@dnax.org
Meng
Gloria
G
Liu
Jun
J
Hurst
Amy
A
Hsei
Vanessa
V
Wong
Wai-Lee
WL
Ekert
Rene
R
Lawrence
David
D
Sherwood
Steven
S
DeForge
Laura
L
Gaudreault
Jacques
J
Keller
Gilbert
G
Sliwkowski
Mark
M
Ashkenazi
Avi
A
Presta
Leonard
L
D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D000915:Antibody Affinity; D018951:Antigens, CD20 / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology; D001666:Binding Sites, Antibody; D002460:Cell Line; D005110:Extracellular Space / Q000276:immunology / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D007128:Immunoglobulin Fragments / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D008297:Male; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism; D013347:Subcellular Fractions / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D007140:Immunoglobulin Fab Fragments; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; D018719:Erb-b2 Receptor Tyrosine Kinases; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C505639:TNFRSF10B protein, human; C505644:Tnfrsf10b protein, rat; C055966:immunoglobulin Fv