Impact of human neutralizing antibodies on antitumor efficacy of an oncolytic adenovirus in a murine model

Clin Cancer Res. 2004 Nov 1;10(21):7199-206. doi: 10.1158/1078-0432.CCR-04-0765.

Abstract

Purpose: 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.

Experimental design: 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.

MeSH terms

  • Adenoviridae / genetics*
  • Animals
  • Body Weight
  • Cell Line, Tumor
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Gene Transfer Techniques*
  • Genetic Therapy / methods*
  • Genetic Vectors
  • Humans
  • Mice
  • Mice, Nude
  • Mice, SCID
  • Neoplasm Transplantation
  • Polymerase Chain Reaction
  • Time Factors
  • beta-Galactosidase / genetics

Substances

  • beta-Galactosidase