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ANGIOSTOP<br />
Novel Anti-angiogenic treatment<br />
for <strong>Cancer</strong>, Arthritis and Ocular<br />
Neovascularization based on Inhibition<br />
of Placental Growth Factor (PlGF)<br />
Summary<br />
ANGIOSTOP proposes an approach to develop a new, safer<br />
and more eff ective anti-angiogenic medicine that reduces<br />
the pathological blood vessel formation associated with<br />
solid tumor growth, ocular neovascularization (diabetic<br />
retinopathy and macular degeneration) and rheumatoid<br />
arthritis. The proposed drug target is Placental Growth<br />
Factor (PlGF) and the candidate drug is a humanized neutralizing<br />
monoclonal antibody. This drug target selection<br />
is based on recent basic research on the role of PlGF in<br />
pathological angiogenesis and ‘translational research’ that<br />
established proof of concept in experimental animal models.<br />
Using a lead candidate anti-PlGF antibody, it has been<br />
demonstrated that inhibition of PlGF reduces solid tumour<br />
growth, inhibits ocular neovascularization and alleviates<br />
arthritis symptoms. ANGIOSTOP will assure the development<br />
of an anti-PlGF antibody that may constitute a new,<br />
safer and effi cacious medicine for the treatment of diseases<br />
that depend on PlGF driven angiogenesis such as cancer,<br />
ocular disease and arthritis.<br />
Problem<br />
Keywords | Angiogenesis | cancer | ocular disease | arthritis | PlGF |<br />
Most anti-angiogenic strategies are focused on blocking<br />
the interaction between VEGF and its receptor VEGFR-2.<br />
Despite the success of Avastin, it is unlikely that VEGFinhibitors<br />
alone will be suffi cient to halt tumour angiogenesis.<br />
Firstly, an increasing number of studies document that<br />
blocking the VEGF pathway leads to the induction of alternative<br />
angiogenic signals. Secondly, it has been reported<br />
that treatment of cancer patients with Avastin signifi cantly<br />
upregulates the levels of PlGF. Finally, the currently available<br />
angiogenesis inhibitors have serious side eff ects thus<br />
mandating the development of additional angiogenesis<br />
inhibitors. Due to the potential application of angiogenesis<br />
inhibitors in disorders other than cancer, where the treatment<br />
is expected to start at earlier times after the disease<br />
onset and continue for longer periods, safer anti-angiogenic<br />
drugs without the risk of serious side eff ects are needed. By<br />
gene targeting study in mice, it has been shown that loss of<br />
PlGF does not cause any vascular defect during development,<br />
reproduction or normal adult life, while it severely<br />
im pairs angiogenesis and arteriogenesis during pathological<br />
conditions including ischemia, infl ammation and cancer<br />
therefore indicating that the ANGIOSTOP anti-angiogenic<br />
strategy targeting PlGF could represent a safer and more<br />
eff ective approach.<br />
Aim<br />
ANGIOSTOP aims to elaborate a comprehensive approach<br />
to the accelerated development of new effi cacious and safer<br />
anti-angiogenic medicines that reduce the pathological<br />
blood vessel growth and can be used for the treatment of<br />
major progressive disorders such as cancer, ocular neovascularization<br />
(as observed in diabetic retinopathy and<br />
age-related macular degeneration) and arthritis. The overall<br />
objective of ANGIOSTOP is to develop an anti-PlGF monoclonal<br />
antibody. The roadmap comprises ‘translational<br />
research’ to validate previous proof of concept studies in<br />
new therapeutically relevant small animal models, both in<br />
terms of safety and effi cacy, to evaluate PlGF expression<br />
and its possible upregulation in cancer patients, and to<br />
develop an industrial production process at the GMP level<br />
for critical path development.<br />
We aim to perform extensive validation studies of our<br />
drug candidate to reduce the risk of failure as the drug<br />
advances into clinical trials and to manufacture this product<br />
for clinical trials. The ultimate goal of ANGIOSTOP is<br />
to develop an anti-PlGF monoclonal antibody for the safe<br />
and eff ective treatment of cancer, ocular disease and<br />
arthritis. The research will focus on a selected drug candidate<br />
but the new models and strategies will be of more<br />
general utility for the development of new medicines<br />
aimed at increasing or reducing blood vessel formation as<br />
well as for the advancement of our understanding of<br />
pathologic angiogenesis.<br />
Expected results<br />
• A lead humanized anti-PlGF antibody will be validated in<br />
appropriate animal models.<br />
• Toxicology studies will identify a safe clinical dose and<br />
document the cross-reactivity profi le and any toxic<br />
eff ects of the lead candidate antibody.<br />
• Process development and industrial GMP manufacturing of<br />
the lead candidate antibody for critical path development<br />
will be carried out.<br />
• The protein expression of PlGF will be examined in patient<br />
tumour samples. If PlGF levels correlate with certain<br />
tumour types and associate with grade and prognosis,<br />
such information may be benefi cial for identifi cation of<br />
appropriate patients groups.<br />
• Development of a fully human back-up antibody with<br />
a similar or better pharmacological profi le as compared<br />
to the lead candidate antibody will be performed for<br />
contingency purposes.<br />
164 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
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