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PEPTIDE TRENDS AUGUST 2016

MEET US THE ANNUAL BOULDER PEPTIDE SYMPOSIUM

The Annual Boulder Peptide Symposium is a unique forum for professionals from pharma, biotech and academia to meet and discuss key challenges in peptide therapeutics. The Symposium draws key scientific decision makers and C-level personnel to learn about new developments and share cases studies in peptide science. The symposium also features a Peptide Showcase which draws many startup and emerging companies interested in presenting to large pharma. 

 

It is our pleasure to inform you that we will be attending the Annual Boulder Peptide Symposium, which will take place September 26 – 29, 2016, at booth #3 at the St. Julien Hotel and Spa in Boulder, CO. We would like to meet with you to discuss how Bachem can help you with your peptide API custom manufacturing needs.

 

Bachem‘s pipeline contains more than 200 customer projects in preclinical and clinical phases. They all have promising potential: in the last two years, a number of products in phase III trials received marketing authorization and phase II projects progressed to pivotal phase III clinical trials. Some of our services include pegylated peptides, lipidated peptides, various other peptide conjugates, and sterile fill and finish (Clinalfa®).

 

A new service in our portfolio is the selective chemical glycosylation. The technology is applicable to large scale and has the potential to be applied to a variety of peptides, where we can pioneer the concept of improving current and future drugs. To view our recent webinar please click here.

 

Setting Specifications for Therapeutic Peptides in Clinical Development will be presented by Daniel Samson, Senior Director API Manufacturing, Bachem AG at St. Julien Hotel & Spa, Xanadu Ballroom, on September 28, 2016 at 2:00 PM.

 

As the Industry leader and pioneering partner, we promise to meet the expectations of our customers. We would be glad to arrange a meeting with you at Boulder Peptide Symposium.

 

To schedule a personal meeting in advance please contact us.

PEPTIDES IN MOLECULAR IMAGING AND NUCLEAR MEDICINE

Molecular imaging probes are important tools in nuclear medicine. Early disease detection, characterization and monitoring of disease progression and therapeutic responses are the main applications.

The use of imaging probes based on radiolabeled small molecules or macromolecules has been limited by low specificity (small molecules) or limited target permeability (monoclonal antibodies). Peptides have been increas­ingly considered as imaging probes, due to their distinctive advantages over small molecules or macromolecules. Peptides can act as a radionuclide carrier in Peptide Receptor Radionuclide Therapy (PRRT).

Due to their ability to bind to different receptors and also being part of several biochemical pathways, peptides act as potential diagnostic tools and biomarkers in disease (e.g. cancer) progression. Peptide receptors such as somatostatin (SST), integrin, gastrin-releasing peptide (GRP), cholecystokinin (CCK), neurotensin (NT), glucagon-like peptide-1 (GLP-1), and neuropeptide-Y (NPY) receptors have been successfully identified and characterized for tumor receptor imaging. Additionally, a number of bioactive peptides and peptide hormones have been discovered through combinatorial peptide chemistry and phage display technology. Such peptides generally have high affinities and specificity for their target and are active at low nanomolar concentrations.

 

Design of peptide-based probes for targeting peptide receptors

Peptides could be directly or indirectly labeled with a wide range of imaging moieties by different chemistries for use as in vivo probes. Radionuclides attached to peptides have been employed for positron emission tomography (PET) or single photon emission computed tomography (SPECT). Near-infrared (NIR) fluorescent dyes or quantum dots attached to peptides can be used for optical imaging. Paramagnetic agents attached to peptides are used for magnetic resonance imaging (MRI). In all these techniques the role of the peptide is to carry the probe to the specific receptor target.

Most neuroendocrine tumors (NETs) feature a strong overexpression of somatostatin receptors, mainly of subtype 2 (sst2). Currently, five somatostatin receptor subtypes (sst) are known (sst1-5). The density of these receptors is vastly higher than on non-tumor tissue. Therefore, somatostatin receptors are attractive targets for delivery of radioactivity via radiolabeled somatostatin analogs. Introduced in the late 1980s, [111In-DTPA]-octreotide ([111In]-pentetreotide, OctreoScan®), the first available radiolabeled somatostatin analog, rapidly became the gold standard for diagnosis of sst-positive NETs. An octreotide scan or octreoscan is a type of scintigraphy used to find carcinoid and other types of tumors and to localize sarcoidosis. [111In-DTPA]-octreotide is a synthetic analog of somatostatin carrying a chelating moiety and radiolabeled with indium-111. Injected into a vein the tracer travels through the bloodstream. The radioactive octreotide attaches to tumor cells that have receptors for somatostatin. A radiation-measuring device detects the radioactive octreotide and produces images showing where the tumor is located in the body.


Figure 1: Radionuclide-labeled peptide binds to receptor on cancer cell surface and enters into the cell, followed by emission of radiation that destroys DNA and cancer cell.

 

Peptide receptor radionuclide therapy (PRRT) combines octreotide (or other somatostatin analogs) with a radionuclide (a radioactive isotope) to form highly specialized molecules called radiolabeled somatostatin analogs or radiopeptides. Radiolabeled somatostatin analogs generally comprise three main parts: a cyclic octapeptide (e.g., octreotide), a chelator (e.g., DTPA, DOTA), and a radionuclide (68Ga, 111In, 90Y, or 177Lu). These radiopeptides can be injected into a patient and will travel throughout the body binding to carcinoid tumor cells that have receptors for them. Once bound, these radiopeptides emit radiation and kill the tumor cells they are bound to (see Figure 1). A few examples of radiolabeled peptide in clinical trials are shown in Table 1.

 

Radiolabeled Peptide

Peptide Receptor

Indication

111In-DTPA-octreotide

SST-Somatostatin

Neuroendocrine tumors

Nα-(1-deoxy-D-fructosyl)-Nε-(2-[18F]-fluoropropionyl)-Lys0,Tyr3-octreotate (18F-[Gluc-Lys]-TOCA)

SST-Somatostatin

Neuroendocrine tumors

[18F]-galacto-RGD

Integrin

Head and neck cancer

[18F]-RGD-K5

Integrin

Various cancers

[99Tc]-Me2Gly-Ser-Cys-Gly-5Ava-Bombesin (7-14)

([99Tc]-RP-527)

GRP

Breast cancer

[111In]-[DTPA-Lys40]-Exendin-4

GLP-1

Insulinoma

Table 1: Examples of radiolabeled peptide probes in clinical trials.

 

In addition to our thousands of catalog peptides, we offer comprehensive custom synthesis services. If the peptide you require is not available at shop.bachem.com, please contact us.

 

References

Thundimadathil, J., Cancer treatment using peptides: current therapies and future prospects, J. Amino Acids 2012, ID 967347 (2012)

Lee, S. et al., Peptide-based probes for targeted molecular imaging, Biochemistry 49, 1364 (2010)

SOMATOSTATIN ANALOGS IN CANCER THERAPY

Apart from the use of peptidic LHRH agonists and antagonists for treating cancer, somatostatin analogs are the only approved cancer therapeutic peptides in the market. Potent agonists of somatostatin (SRIF) including octreotide (sandostatin) have been developed for the treatment of acromegaly, gigantism and thyrotropinoma associated with carcinoid syndrome, and diarrhea in patients with vasoactive intestinal peptide-secreting tumors (VIPomas). Lanreotide, another long-acting analog of somatostatin, is used in the management of acromegaly and symptoms caused by neuroendocrine tumors.

Most neuroendocrine tumors (NETs) feature a strong overexpression of somatostatin receptors, mainly of subtype 2 (sst2). Currently, five somatostatin receptor subtypes (sst) are known (sst1-5). The density of these receptors on tumor tissue is vastly higher than on healthy tissue. Therefore, sst are attractive targets for delivery of radionuclides employing appropriately modified somatostatin analogs. Introduced in the late 1980s by Sandoz, [111In-DTPA]-octreotide (pentetreotide, Octreoscan®), rapidly became the gold standard for diagnosis of sst-positive NETs. Numerous peptide-based tumor-imaging agents targeting sst have been developed over the past decades. Octreoscan® and NeoTect® (technetium-99m-labeled depreotide, cyclo(MePhe-Tyr-D-Trp-Lys-Val-Hcy(CH2CO- β-Dap-Lys-Cys-Lys-NH2)) are the only radiopeptide tracers on the market approved by the FDA. An octreotide scan or octreoscan is a scintigraphic method used to find carcinoids and other types of tumors and to localize sarcoidosis. DTPA-Octreotide, after radiolabeling with indium-111, is injected into a vein and travels through the bloodstream. The radioactive octreotide attaches to tumor cells that have receptors for somatostatin. A radiation-measuring device detects the radioactive octreotide, and generates images showing the precise location of the tumor in the body.

The principle also works in cancer therapy. Peptide receptor radionuclide therapy (PRRT) combines appropriately modified octreotide with a radionuclide, which will bind to carcinoid tumor cells with overexpressed somatostatin receptors. Once bound, the targeted radiation will kill the malignant cells the peptide is bound to.

The complex between radionuclide and peptide has to be stable, especially if the radiopeptide is used in therapy. Cyclic chelators as DOTA bind (radio)nuclides as 68Ga, 90Y, or 177Lu more tightly, so (Tyr3)-DOTA-octreotide (DOTATOC, edotreotide) can be used in diagnosis and therapy of NETs. This also holds true for the C-terminal acid, DOTA-octreotate (DOTATATE).

 

 

Figure 1: Chemical structure of DOTA-octreotate

 

Somatostatin agonists vary in receptor selectivity: Lanreotide shows high affinity for sst2 and somewhat less to sst5. Pasireotide, another SRIF agonist, binds less selectively and thus mimics the natural ligand more closely.

 

References

Bachem monograph Peptides in Cancer Research, 2012436 published by Global Marketing, Bachem Group (2015)

MEET BACHEM: HÉLÈNE RINDLISBACHER, WORKING STUDENT

PT: What is your official job title at Bachem?

Hélène: My official title at Bachem is “Working student”.

 

PT: How long have you been with Bachem?
Hélène: I am almost two years with Bachem. Before Bachem I had different jobs.

 

PT: Briefly, what do you do at Bachem?

Hélène: I do many different things. Basically I help wherever I can. This makes my job interesting and diversified.

 

PT: What is your academic background?

Hélène: I will be an archaeologist in a few years.

 

PT: How is the Marketing & Sales team partnering with their customers?

Hélène: Trough good communication and always doing its best to fulfill and even excel the customers’ expectations.

 

PT: What makes a perfect day for you?

Hélène: A perfect day is a day without any kind of worries. Relaxed, happy, carefree.

 

PT: Have you had any particular expectation when you came to Bachem and have these been fulfilled?

Hélène: No, I didn’t have any. But I am very happy I got this job. It’s the best job a student can think of and Bachem is very flexible when I need more (or less) time for the University.

 

PT: What do you do for fun?

Hélène: Baking is one of my favorite occupations. I also do sports and I like reading.

 

PT: What is your preferred peptide?

Hélène: My favorite peptide is Ghrelin, because it regulates the sense for hunger.


PT: Thank you very much Hélène.

Literature Citations

Bachem peptides and biochemicals are widely cited in research publications. Congratulations to all our customers with recent publications!

 

 

Aleksic, D. et al.

Convergent evolution of pregnancy-specific glycoproteins in human and horse.

Reproduction 152(3): 171-184 (2016).

http://www.ncbi.nlm.nih.gov/pubmed/27280409

 

Inda, C. et al.

Different cAMP sources are critically involved in G protein-coupled receptor CRHR1 signaling.

J. Cell Biol. 214(2): 181-195 (2016)

http://www.ncbi.nlm.nih.gov/pubmed/27402953

 

Lossow, K. et al.

Comprehensive Analysis of Mouse Bitter Taste Receptors Reveals Different Molecular Receptive Ranges for Orthologous Receptors in Mice and Humans.

J. Biol. Chem. 291(29): 15358-15377 (2016)

http://www.ncbi.nlm.nih.gov/pubmed/27226572

 

Tcherniuk, S. et al.

Formyl Peptide Receptor 2 Plays a Deleterious Role During Influenza A Virus Infections.

J Infect Dis 214(2): 237-247 (2016)

http://jid.oxfordjournals.org/content/early/2016/03/30/infdis.jiw127.abstract

 

Wewer Albrechtsen, N. J. et al.

Dynamics of glucagon secretion in mice and rats revealed using a validated sandwich ELISA for small sample volumes.

Am J Physiol Endocrinol Metab 311 Met(2): E302-309 (2016)

http://ajpendo.physiology.org/content/311/2/E302