shown in Figure 1: Gene Transfer-Based Immunotherapeutics: HTV-IT 
(V). 
4.2.4 Summary of Preclinical Research and Toxicology/ Pharmacology 
Studies 
4.2.4. 1 Beginning in September, 1990, Viagene and the scientific staff at the 
4. 2. 4. 2 
FDA's Center for Biologies (CBER) worked jointly to develop a 
comprehensive toxicology/pharmacology plan to evaluate HIV-IT (V). 
Studies were designed for Rhesus macaques monkeys and mice in order 
to address issues of safety, toxicity, potential tumorigenicity, and 
biologic activity. 
Initial preclinical pharmacology studies were conducted in a mouse 
model. The mouse system has been used to evaluate the induction of 
humoral and cellular immune responses due to direct administration of 
HTV-IT (V) or syngeneic cells transduced with HIV-IT (V). Briefly, 
mice were immunized with a series of HTV-IT (V) injections and anti- 
HTV- 1 ENV specific CD8 + CTL responses were analyzed (Figure 2). 
HTV-IT-treated murine cells injected into mice induced a strong CTL 
response directed against target cells expressing the HTV-Itttr envelope 
protein (BCenv), whereas no significant lysis of the control BC cells 
was observed. 
4. 2.4. 3 
HTV-IT (V) has consistently elicited substantial CTL responses in mice. 
In this model system, multiple immune response parameters have been 
examined in detail. These include (1) single vs. multiple injections, (2) 
route of administration, (3) phenotype of the effector population, (4) 
MHC restriction, and (5) the specificity of the immune response with 
regard to ENV, REV and NEO^ determinants. 
4. 2. 4. 4 
Although HIV-IT (V)-transduced cells express the env gene from 
HIV-lmB it is known that the HIV-MN prototypic laboratory viral 
strain is a more serologically representative strain in patients^. Data 
are presented in Figure 3 demonstrating that mice immunized with HTV- 
IT (V) encoding the env gene from the laboratory strain HTV-lrrTR 
induce CTL which recognize and lyse cells expressing not only the 
homologous HIV-lmB strain, but also lyse cells coated with a peptide 
^Devash, Y., et al, AIDS Res. &. Human Retroviruses, 6:307-316 (1990). 
Recombinant DNA Research, Volume 17 [899] 
