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Products and technology
Thorium
The Thorium platform – new potential opportunities for
­alpha-pharmaceuticals
An important objective for Algeta during 2010 has been to develop and implement a strategy
with the aim of building a future pipeline of novel targeted cancer product candidates
beyond Alpharadin®. This strategy leverages Algeta’s world-leading expertise and intellectual property around the use of alpha-emitters and its targeted therapeutic approach for
the treatment of cancer.
Initially, Algeta is focused on the
development of the Thorium platform
with the aim of building additional
product opportunities based on its
alpha-pharmaceutical platform and its
targeted therapeutic approach for the
treatment of cancer.
This work is at an early preclinical
feasibility stage, however Algeta believes
that alpha-emitters have the potential
to offer a number of unique advantages
over conjugated cytotoxic drugs as the
payloads in targeted cancer therapies
that may lead to an enhanced clinical
effect. These benefits include increased
potency and an ability to overcome drug
resistance by virtue of their direct tumorkilling mechanism of action (see page
16).
Thorium-227, which forms the basis of
Algeta’s second alpha-pharmaceutical
platform, is a radionuclide that emits
high-energy alpha particles, but is not
inherently tumor-targeting. However, by
linking thorium-227 to tumor-targeting
molecules such as monoclonal anti­
bodies, Algeta has the potential to create
preclinical candidates for a future
pipeline of novel alpha-pharmaceuticals
that specifically seek and destroy cancer
cells while minimizing damage to
surrounding healthy tissues. The process
is shown schematically in the figure
below.
Market opportunity
There is increasing focus by drug
companies on the development of
next-generation targeted cancer
therapeutics where cancer-killing
payloads are attached to ‘naked’
tumor-targeting antibodies, in an
attempt to maximize the effectiveness
of therapy.
Conjugation of thorium-227 to targeting
molecules has the potential to enhance
the effectiveness of treatment for a wide
and broad variety of cancer types.
Therefore, the technology has the
potential to generate variety of proprietary drug candidates for development
by Algeta.
Proof of Concept
Preclinical data supporting this concept
have been presented at scientific
conferences in recent years, including
at the European Association of Nuclear
The Goals of Targeted Alpha Therapy
Monoclonal antibody
(mAb)
Cancer cell
Tumor-targeting thorium-227 conjugate
The short range of alpha particles kills cancer cells
within 2–10 cell diameters.
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Medicine meeting in October 2010. In
these studies, Algeta and its academic
collaborators have generated promising
results that demonstrate the targeted
cancer cell-killing effect of thorium-227
conjugated to tumor-targeting antibodies
such as trastuzumab and rituximab in
validated models of breast cancer and
lymphoma, respectively.
Using the HER-2 monoclonal antibody
trastuzumab as an example, the studies
have demonstrated:
• Target specificity: thorium-227-trastuzumab selectively targeted and bound
HER-2 presenting tumor cells in vitro
and in mice with HER-2 positive
tumors
• Tumor cell-killing effect: thorium227-trastuzumab exerted a measurable and dose-dependent therapeutic
effect by killing HER-2 positive breast
cancer cells to which it was bound and
had a significant effect on tumor
growth at low doses
• Indication of safety: blood toxicity of
thorium-227-trastuzumab, determined
from measuring white blood cell
counts in the mouse models, was
modest and temporary. This is
believed to be a result of the targeted
and localized mode of action of
thorium-227-trastuzumab.
Advancing the Platform
The ability to link thorium-227 to
tumor-targeting molecules is funda­
mental for the development of these
new alpha-pharmaceuticals. Algeta has
significant expertise in binding (chelating) thorium-227 and conjugating it to
the tumor-targeting molecules having
already demonstrated proof of concept
of such conjugates using non-proprietary chelators as noted above.
In October 2010, in order to further
improve the attachment of thorium-227
to the tumor-targeting molecules, Algeta
entered into a technology access
agreement with Lumiphore, Inc.
(Richmond, CA, USA). The agreement
provides Algeta with exclusive access
to the US firm’s novel, patented Lumi4®
chelator technology, which will be
evaluated for its ability to bind thorium­227 and link it to tumor-targeting
molecules.
Under the option agreement, Algeta will
assess whether the Lumi4® technology
offers advantages that could produce
enhanced conjugates when compared
Products and technology
Annual Report 2010
to those successfully employed in the
previous thorium-227 feasibility studies.
Key benefits may include more rapid,
efficient and cost-effective chelation and
conjugation processes, and increased
conjugate stability. In addition, use of the
technology if applied successfully, is
anticipated to extend Algeta’s proprietary
position around its Thorium platform.
Development team strengthened
In a further move to accelerate the
development of its Thorium platform,
Algeta appointed Dr. Lars Abrahmsén
as Senior Vice President, Protein
Therapeutics. Dr. Abrahmsén was
previously CSO of Affibody AB, a Swedish
company developing proprietary
tumor-targeting molecules for thera­
peutic and diagnostic purposes. He has a
wealth of experience in protein engineering, including monoclonal antibody
production and conjugation, gained at
Affibody, Genentech and Pharmacia.
Over the past 20 years, working primarily
in oncology, Dr. Abrahmsén has led
several projects from discovery through
preclinical development and into the
clinic, building expertise in technologies
for conjugation of therapeutic payloads
to monoclonal antibodies and other
targeting mole­cules.
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