<PAGE>
EXHIBIT 99.1
Abstract
Adenovirus targeting deregulation of the RB tumor suppressor pathway in cancer
cells demonstrate potent anti-tumor activity.
L. Johnson, A. Sampson-Johannes, S. McCoy, J. Holt, T. Hermiston and A. Fattaey.
Onyx Pharmaceuticals, Inc., Richmond, CA 94806
We have developed human adenoviruses that selectively replicate based upon
deregulation of the pRb-signaling pathway in human cancers. Disruption of
this signaling cascade has been linked to a variety of different tumor types
and can occur through genetic alteration of a number of different components
that lie within this pathway (e.g., p16, cdk4, cyclin D and pRb). Through its
binding to cellular transcription factors such as E2F, pRb and its associated
proteins can function as a transcriptional repressor complex that regulates
cell cycle progression regardless of the tissue of origin of the infected
cells. For human adenoviruses, one function of their E1A proteins is to
sequester pRb and its related family members, thereby rendering the cell
permissive to both viral and cellular DNA synthesis. The human adenovirus,
ONYX-838, encodes a mutant E1A gene whose products are no longer capable of
binding to and inactivating pRb. We have further engineered ONYX-838 to
create a series of viruses whose early gene expression patterns are dependent
upon abnormal E2F activity as a result of deregulated pRb pathway signaling.
These viruses have demonstrated anti-tumor activity similar to wildtype human
adenovirus both IN VITRO and IN VIVO. The E2F-dependent regulation engineered
into these viruses has significantly reduced the expression of certain early
genes in normal human primary cells, regardless of their proliferative state,
and underscores the tumor cell selectively built into these viruses. This
marked decrease in early gene expression translates into reduced late gene
expression and an attenuated viral infection. The very limited toxicity that
is associated with these viruses in normal, human primary cells IN VITRO is
also observed IN VIVO and may have important safety implications following
systemic administration. This strategy to combine alterations in E1A with
E2F-dependent regulation of early viral gene expression has yielded
therapeutic viruses that are both safe and highly selective for the loss of
an intact pRb pathway in human cancers.
Introduction
We have exploited the use of selectively replicating viral therapy to engineer
and develop human adenoviruses that will replicate based upon deregulation of
the pRb-signaling pathway in human cancers. Disruption of this signaling cascade
has been linked to a variety of different tumor types and can occur through
genetic alteration of a number of different components that lie within this
pathway (e.g., p15, cdk4, cyclin D and pRb). Through its binding to cellular
transcription factors such as E2F, pRb and its associated proteins can function
as a transcriptional repressor complex that regulates the expression of
E2F-responsive genes and, hence, cell cycle progression regardless of the tissue
of origin of the infected cells. For human
<PAGE>
adenoviruses, one function of their E1A proteins is to sequester pRb and its
related family members, thereby rendering the cell permissive to both viral
and cellular DNA synthesis. The human adenovirus, DL922/47 (ONYX-838),
encodes a mutant E1A gene whose products are no longer capable of binding to
an inactivating pRb. We have engineered further ONYX-838 to create a series
of viruses whose early gene expression patterns are dependent upon abnormal
E2F activity as a result of deregulated signaling within the pRb pathway.
These viruses have demonstrated anti-tumor activity similar to wild-type
human adenovirus both IN VITRO and IN VIVO. The E2F-dependent regulation
engineered into these viruses has significantly reduced the expression of
certain early genes in normal human primary cells, regardless of their
proliferative state, and underscores the tumor cell selectivity built into
these viruses. This marked decrease in early gene expression translates into
drastically reduced late gene expression and an attenuated viral infection.
The very limited toxicity that is associated with these viruses in normal,
human primary cells IN VITRO is also observed IN VIVO and may have important
safety implications following systemic administration. This strategy to
combine alterations in E1A and E2F-dependent regulation of early viral gene
expression has yielded therapeutic viruses that we believe are both safe and
selective for the loss of an intact pRb-pathway in human cancers.
Summary
The enhanced selectivity of the E1A and E2F-dependent viruses results in a
substantially increased therapeutic index in animal models of human cancer.
The RB-targeted Adenoviruses demonstrate efficacy that:
The RB-targeted Adenoviruses demonstrate activity that is responsive to the
functional status of pRb.
The RB-targeted Adenoviruses demonstrate enhanced safety, both IN VIVO and IN
VITRO, compared to wild-type Adenovirus, with restricted expression/activity
regardless of their proliferative status.
Onyx currently plans to file an IND by the end of 2001 to test the
RB-targeted viruses in a human clinical trial for the treatment of cancer.
FORWARD-LOOKING STATEMENT
This abstract contains certain forward-looking statements regarding the
development of potential human therapeutic products that involve a number of
risks and uncertainties. Actual events may differ from Onyx's expectations.
