DESCRIPTION (Applicant's Description) The long-term objective of this
research project is to define the role of human papillomavirus type (HPV) 16
E6 and E7 oncoproteins in cervical carcinogenesis. Human papillomavirus
type 16 E6 and E7 are viral oncoproteins that are believed to play a major
role in the development of cervical neoplasia. Data from our previous
studies demonstrated that anti-E7 intracellular single-chain antibodies
(scFvs) have the ability to inhibit cell proliferation in HPV 16-positive
human cervical carcinoma cell lines by 85 to 95 percent, and to strongly
downregulate the level of HPV 16 E7-specific protein. HPV 16-negative cell
lines were unaffected.
HPV 16 E6 also plays a major role in development of cervical cancer, and may
be an ideal target gene to knock out. The hypothesis to be tested in this
pilot study is that knock-out of HPV 16 E6 and E7 using scFvs against these
oncoproteins will inhibit cervical cancer cell proliferation and
down-regulate expression of these oncoproteins in vitro. The first
objective will be to construct scFvs against the HPV 16 E6 oncoprotein, and
to use the scfvs to a) direct expression of intracellular anti-HPV 16 E6
antibodies in human cervical carcinoma cell lines, and b) knock-out HPV 16
E6 oncoprotein in HPV-positive cell lines. The second objective is to make
an intracellular single-chain bispecific antibody [bs(scFv)2] composed of
anti-E6 and - anti-E7 to simultaneously knock out E6 and E7 oncoproteins in
vitro. It is hypothesized that bs(scFv)2 will be more effective than either
single scFv in inhibiting cell proliferation.
HPV infection is a causative factor in over 90 percent of cervical cancers
worldwide, and the oncogenic function of HPV has been assigned to the E6 and
E7 genes. The ability to inhibit expression of these oncoproteins would
thus be expected to decrease the incidence of cervical cancer. If the in
vitro studies proposed here employing anti-HPV 16 E6 and E7 intracellular
single-chain antibodies are successful, they will provide supporting data
for future in vivo studies using these antibodies in nude mice, as well as
future clinical and nutritional studies aimed at inhibiting cervical tumor
progression via anti-gene therapy.
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