Based on their current level of understanding of the mechanisms of action, scientists have shown that these IGFBPs are involved actions beyond their endocrine role in IGF transport. In the pericellular and intracellular compartments, for example, IGFBPs are instrumental in the regulation of cell growth and survival.
IGF and Cancer
Over the last decade, IGF has gained tremendous
interest because it plays an important role in cancer. Conventional
chemotherapy for the treatment of patients with cancer has limited specificity
for cancer cells. In these cases, high doses of systemic chemotherapy used to
treat patients have limited success and these patients experience significant
side effects.
With the shift towards targeted therapies, a number of
strategies have been exploited to target tumors directly. The most common of
these strategies involves engineered antibodies or antibody fragments. The
increased interest in IFG and cancer and this drive to targeted therapies, has
resulted in strategies targeting various components of the IGF system [2].
Insulin-like growth factor-1 receptor or IGF-1R activation is involved in cell regulation, survival and proliferation. In
advanced cancers IGF-IRs are frequently genetically altered involving mutation,
chromosomal translocation, abnormal stimulation, and loss of genomic
imprinting. High levels of IGF-1 have been reported in several cases of breast
and prostate cancers[1][2].
Insulin-like growth factor-binding protein-3
Insulin-like growth factor-binding protein-3 or IGFBP‐3, first isolated, characterized, and quantitated in
human plasma, in 1986, is the main IGF transport protein in the bloodstream
directly influencing IGF action. [3][4] Via independent mechanisms involving
interactions with plasma, extracellular matrices and cell surface molecules,
conditional proteolysis, cellular uptake, and nuclear transport, IGFBP-3 also
modulates IGF actions indirectly[5].
IGFBP-3, which in plasma is known to participate in
high-affinity interactions with the iron-binding proteins lactoferrin and transferrin,
has been implicated with a variety of proteins or signaling cascades critical
to cell cycle control and apoptosis.
Antiproliferative and proapoptotic effects of IGFBP-3,
independent from IGF/IGF-IR, contribute to improving the pathophysiology of a
variety of human diseases, such as cancer, as well as diabetes, and
malnutrition[6][7][8].
Metal-binding transporter domain
The amino acid metal-binding transporter domain or MBD
derived from IGFBP‐3 selectively targets cancer cells. In a number of studies
scientists have demonstrated that MBD-tagged anti-cancer peptides can have
cytotoxic effects on a broad range of human cancer cell lines. In one of these
studies, researchers investigated the discriminant validity of the molecules as
potential co-therapeutic agents. By comparing their cytotoxicity to cancer cell
lines versus normal human cell counterparts, the researchers demonstrated
synergies between these molecules and marginally cytotoxic levels of
5-fluorouracil[6].
Biodistribution data from in-vivo experiments
in normal mice and rats further confirmed that MBD-tagged moleculespreferentially
localize to specific tissues including the kidney and pancreas and
significantly reduced splenomegaly and bone marrow cancer cell burden in
diseased animals. This suggests that MBD-tagged molecules can be used as highly
selective chemosensitizers in the treatment of hematological and disseminated
malignancies.
Functionalizing MBD
To enhance the ability of antibody-drug conjugates to
target and deliver payloads directly to tumor cells, Goodwin Biotechnology,
Inc., a biological Contract Manufacturing Organization or CMO (Plantation, FL)
that specializes in Mammalian Cell Culture expression systems and
Bioconjugation technologies, and Transporin, Inc. (Sunnyvale, CA), a Silicon
Valley R & D company with full ownership of IP rights to a broad array of
life science technologies, have agreed to collaborate on exploring and
functionalizing Transporin’s proprietary metal-binding domain transporter
technology in the development of antibody and peptide-based biopharmaceutical
drugs.
Under the terms of the agreement Goodwin Biotechnology has been granted a worldwide, exclusive license to utilize the proprietary
metal-binding domain of human insulin‐like growth factor binding protein‐3
conjugated to monoclonal antibodies or antibody fusion proteins, and perform
process development and manufacturing services using such conjugates for
research, evaluation, and clinical trial purposes.
Significant development
“This is a significant milestone for our company,”
said Karl Pinto, CEO of Goodwin Biotechnology. “We have been committed to
investing in and advancing the field of Bioconjugation for nearly 15 years, and
this collaboration enables us to offer our clients a proprietary, enabling
technology that promises to enhance the targeting ability of our clients’
antibodies, then enhance the ability for the payload to enter the target cell
where it can do its job. This unique technology is designed to enhance the
therapeutic ratio of efficacy while minimizing side effects and it may also
reduce the cost of therapy—All of which have a positive impact on the quality
of care for patients and their families.”
Proprietary peptides
“Transporin has developed a transporter module
consisting of approximately 20 amino acids based on the metal‐binding domain of
IGF‐binding proteins, which form part of a new generation of proprietary
peptides,” said Desmond Mascarenhas, PhD, CEO of Transporin.
“When covalently attached to other peptides, large
proteins or small nucleic acids, the MBD transporter can deliver these
biomolecules intracellularly, differentiating between normal cells and cells
under stress, and targeting the latter. Possible targets include many types of
cancer, metabolic disease as well as autoimmune conditions. The MBD‐peptide
complex rapidly transports its cargo into cytoplasmic and nuclear compartments
of targeted cells.”
“When augmenting Goodwin Biotechnology’s expertise in
Bioconjugation with our proprietary MBD peptide technology, the potential value
of the resultant conjugate is increased multi‐fold,” Mascarenhas continued.
“There are a number of applications that can be explored. For example, the MBD amino
acid sequence can be incorporated as a linker to bind to a functional
monoclonal antibody to generate an antibody‐linker‐drug conjugate. Another
option is that the MBD peptide sequence can be genetically incorporated into
the DNA sequence of a specific product to develop a unique cell line.”
Great potential
Further, when linking a monoclonal antibody to a
radioactive metal, the MBD peptide sequence can be used as an excipient to bind
the metal and possibly shield the radioisotope to protect healthy cells while
the complex is in circulation while enhancing the ability of the complex to
target diseased cells via a non‐covalent interaction that doesn’t require a
significant drug change.
The ability of the MBD amino acid sequence to bind to
metals, specifically nickel, cobalt, zinc, iron and possibly other metals
(including radioisotopes) may also help enhance the purification process for
difficult‐to‐purify proteinsusing metal‐affinity columns[5]. The MBD‐antibody
conjugate can be used for diagnostic purposes, for monitoring diseases and/or
as a therapeutic modality.
Unmet needs require a new approach
The potential value of the MBD‐peptide technology can
best be appreciated when put in perspective. While modern medicine has made
significant strides in the treatment of a large number of human disease
conditions, including cancer, a number of diseases require advancements to
improve detection, monitoring, and treatment.
Monoclonal antibodies (mAbs) conjugated with a payload
such as a drug or radioisotope are showing some promise based on their ability
to target diseased cells. However, based on the complexity of the antibody:linker:payload
conjugate, premature cleavage of the payload from the conjugate, inability
of the conjugate to breach the cell wall, binding to non‐target sites and/or
getting eliminated from the body prematurely, some researchers suggest that
greater than 95% of the administered dose never reaches the intracellular
target[8].
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