Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index.
Antibody-drug conjugates enhance the antitumor effects of antibodies and reduce adverse systemic effects of potent cytotoxic drugs. However, conventional drug conjugation strategies yield heterogenous conjugates with relatively narrow therapeutic index (maximum tolerated dose/curative dose). Using leads from our previously described phage display-based method to predict suitable conjugation sites, we engineered cysteine substitutions at positions on light and heavy chains that provide reactive thiol groups and do not perturb immunoglobulin folding and assembly, or alter antigen binding. When conjugated to monomethyl auristatin E, an antibody against the ovarian cancer antigen MUC16 is as efficacious as a conventional conjugate in mouse xenograft models. Moreover, it is tolerated at higher doses in rats and cynomolgus monkeys than the same conjugate prepared by conventional approaches. The favorable in vivo properties of the near-homogenous composition of this conjugate suggest that our strategy offers a general approach to retaining the antitumor efficacy of antibody-drug conjugates, while minimizing their systemic toxicity.
Junutula
Jagath R
JR
Genentech Inc, South San Francisco, California 94080, USA.
Raab
Helga
H
Clark
Suzanna
S
Bhakta
Sunil
S
Leipold
Douglas D
DD
Weir
Sylvia
S
Chen
Yvonne
Y
Simpson
Michelle
M
Tsai
Siao Ping
SP
Dennis
Mark S
MS
Lu
Yanmei
Y
Meng
Y Gloria
YG
Ng
Carl
C
Yang
Jihong
J
Lee
Chien C
CC
Duenas
Eileen
E
Gorrell
Jeffrey
J
Katta
Viswanatham
V
Kim
Amy
A
McDorman
Kevin
K
Flagella
Kelly
K
Venook
Rayna
R
Ross
Sarajane
S
Spencer
Susan D
SD
Lee Wong
Wai
W
Lowman
Henry B
HB
Vandlen
Richard
R
Sliwkowski
Mark X
MX
Scheller
Richard H
RH
Polakis
Paul
P
Mallet
William
W
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000494:pharmacology; D000912:Antibodies, Neoplasm / Q000235:genetics / Q000494:pharmacology*; D000918:Antibody Specificity; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D018394:CA-125 Antigen / Q000276:immunology; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003545:Cysteine / Q000235:genetics; D003603:Cytotoxins / Q000494:pharmacology*; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000493:pharmacokinetics*; D008252:Macaca fascicularis; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009842:Oligopeptides / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000276:immunology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D018394:CA-125 Antigen; D003603:Cytotoxins; D000922:Immunotoxins; C451759:MUC16 protein, human; D008565:Membrane Proteins; D009842:Oligopeptides; D013438:Sulfhydryl Compounds; D003545:Cysteine; C495575:monomethyl auristatin E