Impact of human neutralizing antibodies on antitumor efficacy of an oncolytic adenovirus in a murine model.
OBJECTIVE
The purpose of this study was to assess the impact of anti-adenovirus neutralizing antibodies (AdNAbs) on the distribution, tolerability, and efficacy of intravenously administered oncolytic adenovirus. A translational model was developed to evaluate the impact of humoral immunity on intravenous administration of oncolytic adenovirus in humans.


METHODS
Initially, severe combined immunodeficient (SCID)/beige mice were passively immunized with various amounts of human sera to establish a condition of preexisting humoral immunity similar to humans. A replication-deficient adenovirus encoding beta-galactosidase (rAd-betagal) was injected intravenously into these mice. An AdNAb titer that mitigated galactosidase transgene expression was determined. A xenograft tumor-bearing nude mouse model was developed to assess how a similar in vivo titer would impact the activity of 01/PEME, an oncolytic adenovirus, after intravenous administration.


RESULTS
In SCID/beige mice, there was a dose dependence between AdNAbs and galactosidase transgene expression; 90% of transgene expression was inhibited when the titer was 80. A similar titer reconstituted in the nude mice with human serum, as was done in the SCID/beige mice, did not abrogate the antitumor efficacy of the replicating adenovirus after intravenous administration. Viral DNA increased in tumors over time.


CONCLUSIONS
In intravenous administration, preexisting AdNAb titer of 80 significantly attenuated the activity of a 2.5 x 10(12) particles per kilogram dose of nonreplicating adenovirus; the same titer had no affect on the activity of an equivalent dose of replicating adenovirus. Our results suggest that a majority of patients with preexisting adenovirus immunity would be candidates for intravenous administration of oncolytic adenovirus.
Tsai
Van
V
Canji, Inc., San Diego, California 92121, USA. van.tsai@canji.com
Johnson
Duane E
DE
Rahman
Amena
A
Wen
Shu Fen
SF
LaFace
Drake
D
Philopena
Jennifer
J
Nery
Jonathan
J
Zepeda
Monica
M
Maneval
Daniel C
DC
Demers
G William
GW
Ralston
Robert
R
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001835:Body Weight; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D016133:Polymerase Chain Reaction; D013997:Time Factors; D001616:beta-Galactosidase / Q000235:genetics
D001616:beta-Galactosidase