In Vitro Characterization of Human Cytomegalovirus-Targeting Therapeutic Monoclonal Antibodies LJP538 and LJP539.
Human cytomegalovirus (HCMV) infection is usually benign in healthy individuals but can cause life-threatening disease in those with compromised immune systems. Approved drugs available to treat HCMV disease, including ganciclovir, cidofovir, and foscarnet, have significant toxicities that limit their use in certain patient populations. LJP538 and LJP539 are human monoclonal antibodies that are being evaluated as immunoglobulin therapeutics. The antibodies target glycoproteins gB and the gH/gL/UL128/UL130/UL131a pentameric complex, respectively. Here we present an in vitro characterization of these antibodies. We show that LJP538 and LJP539 are more potent than a marketed immunoglobulin at inhibiting HCMV infection of various cell lines relevant to pathogenesis. We find that LJP538 and LJP539 are active against a panel of clinical isolates in vitro and demonstrate minor-to-moderate synergy in combination. Passage of HCMV in the presence of LJP538 or LJP539 alone resulted in resistance-associated mutations that mapped to the target genes. However, no loss of susceptibility to the combination of antibodies was observed for >400 days in culture. Finally, the binding regions of LJP538 and LJP539 are conserved among clinical isolates. Taken together, these data support the use of LJP538 and LJP539 in combination for clinical trials in HCMV patients.
Novartis Institutes for BioMedical Research, Infectious Disease Area, Emeryville, California, USA.
Hetalkumar D
HD
Patel
Novartis Institutes for BioMedical Research, Infectious Disease Area, Emeryville, California, USA.
Pavel
P
Nikitin
Novartis Institutes for BioMedical Research, Infectious Disease Area, Emeryville, California, USA Novartis Vaccines, Cambridge, Massachusetts, USA.
Thomas
T
Gesner
Novartis Institutes for BioMedical Research, Infectious Disease Area, Emeryville, California, USA.
James J
JJ
Lin
Novartis Institutes for BioMedical Research, Infectious Disease Area, Emeryville, California, USA.
David T
DT
Barkan
Novartis Vaccines, Cambridge, Massachusetts, USA.
Claudio
C
Ciferri
Novartis Vaccines, Cambridge, Massachusetts, USA.
Andrea
A
Carfi
Novartis Institutes for BioMedical Research, Infectious Disease Area, Emeryville, California, USA.
Tahmineh
T
Akbarnejad Yazdi
Novartis Institutes for BioMedical Research, Infectious Disease Area, Emeryville, California, USA.
Peter
P
Skewes-Cox
Novartis Institutes for BioMedical Research, Infectious Disease Area, Emeryville, California, USA.
Brigitte
B
Wiedmann
Novartis Institutes for BioMedical Research, Infectious Disease Area, Emeryville, California, USA.
Nadine
N
Jarousse
Novartis Institutes for BioMedical Research, Infectious Disease Area, Emeryville, California, USA.
Weidong
W
Zhong
Novartis Institutes for BioMedical Research, Infectious Disease Area, Emeryville, California, USA.
Adam
A
Feire
Novartis Institutes for BioMedical Research, Infectious Disease Area, Emeryville, California, USA christy.hebner@novartis.com.
Christy M
CM
Hebner
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D000914:Antibodies, Viral / Q000276:immunology / Q000494:pharmacology*; D000998:Antiviral Agents / Q000276:immunology / Q000494:pharmacology*; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity*; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D008562:Membrane Glycoproteins / Q000276:immunology; D009154:Mutation; D014759:Viral Envelope Proteins / Q000276:immunology; D053586:Virus Internalization / Q000187:drug effects
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000998:Antiviral Agents; D008562:Membrane Glycoproteins; D014759:Viral Envelope Proteins