WO2012000862A1 - Peptide marqué 11c pour la détection d'un tissu malade - Google Patents

Peptide marqué 11c pour la détection d'un tissu malade Download PDF

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Publication number
WO2012000862A1
WO2012000862A1 PCT/EP2011/060424 EP2011060424W WO2012000862A1 WO 2012000862 A1 WO2012000862 A1 WO 2012000862A1 EP 2011060424 W EP2011060424 W EP 2011060424W WO 2012000862 A1 WO2012000862 A1 WO 2012000862A1
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WO
WIPO (PCT)
Prior art keywords
peptide
diseased tissue
hla
amino acid
carbon atom
Prior art date
Application number
PCT/EP2011/060424
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German (de)
English (en)
Inventor
Oliver Lade
Jan Alexander Hiss
Hartmuth C. Kolb
Ursus KRÜGER
Gisbert Schneider
Arno Steckenborn
Original Assignee
Siemens Aktiengesellschaft
Johann Wolfgang Goethe-Universität
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Siemens Aktiengesellschaft, Johann Wolfgang Goethe-Universität filed Critical Siemens Aktiengesellschaft
Publication of WO2012000862A1 publication Critical patent/WO2012000862A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/531—Production of immunochemical test materials
    • G01N33/532—Production of labelled immunochemicals
    • G01N33/534—Production of labelled immunochemicals with radioactive label

Definitions

  • the invention relates to the use of a peptide for the manufacture ⁇ position of an agent for detecting a diseased tissue. It further relates to a radiopharmaceutical for the localization of a diseased tissue comprising such a peptide. In modern diagnostics are used to characterize
  • the invention is therefore based on the object, an agent be ⁇ riding determine by which a diseased tissue can be specifically and regardless of its size detected.
  • This task is achieved by the use of a peptide solved an agent for the detection of a diseased tissue.
  • the amino acid sequence of the peptide derived from the amino acid sequence of a protein that is formed by the diseased tissue and to a human leukocyte antigen (HLA) complex binds, which is also formed from the morbid tissue ⁇ be, the diseased tissue can be specifically pointed by ⁇ ,
  • HLA human leukocyte antigen
  • peptide refers to an organic compound of at least two amino acids linked via a peptide bond. It includes both oligopeptides of up to about ten amino acids, as well as polypeptides of up to about 30 amino acids, regardless of their primary, secondary or tertiary structure. In this case, both naturally occurring and biotechnologically or synthetically produced compounds are included.
  • the peptide used in the invention is selected so that the amino acid sequence of the peptide derived from the amino ⁇ acid sequence of a protein that is formed by the krankhaf ⁇ th tissue and binds the peptide in a HLA complex, which is also formed from the diseased tissue.
  • HLA complex refers to a transmembrane protein, also called "major It is composed of two polypeptide chains encoded by the human leucocyte antigen, HLA complexes that bind short-chain peptides that are formed in the degradation of both home and foreign proteins in the cell and anchor them to the human leukocyte antigen Zellaußensei ⁇ te.
  • Each HLA complex binds only specific fragments so that the interactions between a fragment and a HLA complex on the size and the amino acid sequence of the peptide are dependent. therefore, the HLA complexes specifically bind to certain peptides therefore, the cell has an. size
  • the peptide used in the invention is derived from the amino acid sequence of a protein and binds to a HLA complex, both of which are formed by the same krankhaf ⁇ th tissue pathological tissue can be detected with the peptide.
  • the amino acid sequence of a fragment derived from a particular protein of the diseased tissue can be determined by isolating HLA fragment complexes from samples of diseased tissue. Subsequently, the bound fragments are separated from the HLA complex by means of "reversed phase HPLC" (WO 2004/085461) and sequenced using mass spectroscopic methods.
  • the peptide is made after the sequence of the fragment and binds specifically to the corresponding HLA complex on the surface of the diseased tissue without binding to HLA complexes of other cells.
  • the peptide is chosen so that the bond between the peptide and the HLA complex has a linear coefficient, called kD value, of ⁇ 100 nM, preferably of ⁇ 10 nM, most preferably of 7.5 nM.
  • kD value linear coefficient
  • HLA complexes include, for example, cells infected with viruses or bacteria, hypertrophic tissue, inflamed tissues and organs, hyperplastic and neoplastic tissue, such as ulcers, tumors and carcinomas.
  • Diseased cells often form proteins whose expression is typical of a particular disease, for example because they are derived from the genetic material of a virus or bacterium. The cell then presents HLA complexes on their surface bind the fragments of these pro ⁇ proteins. By being derived from a disease-specific protein, the peptide specifically binds these HLA complexes and enables reliable localization of the diseased tissue.
  • positrons also referred to as ß + radiation
  • ß + radiation If the positrons hit an electron, they form two photons that are in one
  • An advantage of using an 11 C-labeled peptide is its structure of endogenous amino acids, making it compatible with the organism.
  • the peptide and its a ⁇ individual amino acids are non-toxic, they can naturally metabolized, are broken down and excreted.
  • the use of an integrated 11 C carbon atom also makes it possible to prevent a radioactive foreign substance, such as fluorine, xenon, or gallium, from having to be introduced into the organism.
  • Another advantage of the peptide directly labeled with X1 C lies in the favorable signal / background ratio during the detection of the peptide.
  • the peptide binds to the HLA Kom ⁇ plex, with which it forms a stable, difficult to access for enzymatic degradation, compound. Free, unbound
  • the peptide has about eight to about ten amino acids.
  • the peptide binding site of the HLA complex consists of a deep cleft formed by the N-terminal ends of the two polypeptide chains. It is extremely mobile in its conformation , so that HLA complexes can bind molecules of different sizes. However, the binding affinity is strongest to Pep ⁇ tiden of eight to ten amino acids, so the resulting HLA-peptide complexes are particularly stable and protected against enzymatic degradation.
  • the peptide binds to the peptide binding site of the HLA complex.
  • Human cell h ⁇ len form a plurality of different HLA complexes that bind different types of protein fragments.
  • HLA I and HLA II complexes are distinguished, with HLA I complexes binding, in particular, proteins which originate from the cytoplasm of the cell and HLA II complexes, those which belong to the
  • HLA complexes are again distinguished by the sequence of their polypeptide chains.
  • the binding specificity between an HLA complex and a particular peptide results from the binding column of the HLA complex.
  • the other parts of the complex do not differ greatly among the different types of HLA complexes.
  • the agent is a radiopharmaceutical.
  • radiopharmaceuticals refers to medicines containing radionuclides whose radiation is used for diagnosis and therapy. The main applications are in oncology, Kar ⁇ ogy and neurology, as well as pharmaceutical research.
  • radionuclides are gamma or beta rays emittieren- de nuclides, for example Xenon 133, "technetium, gallium 68, fluorine 18 and used.
  • Kom ⁇ formers such as diethylene triamine pentaacetate (DTPA) 1,4,7, 10- tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA) or ethylenediamine tetraacetate (EDTA) to mono- or polysaccharides bound.
  • DTPA diethylene triamine pentaacetate
  • DOTA tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid
  • EDTA ethylenediamine tetraacetate
  • the nuclides are detected by scintigraphy, single photon emission computed tomography (SPECT) or positron emission tomography (PET), depending on the nature of their radiation.
  • SPECT single photon emission computed tomography
  • PET positron emission tomography
  • a peptide from endogenous amino acids significantly reduces this risk because neither the peptide itself nor its degradation products are toxic. Moreover, it is carbon, unlike Techne ⁇ consortium or xenon, one in the body occurring element that can be metabolized na ⁇ Moslich.
  • the C-carbon atom is a carbonyl carbon atom of an amino acid.
  • the carbonyl groups are part of the peptide bonds between the amino acids and are located inside the peptide. This ensures that the ⁇ C carbon atom is not cleaved off the peptide, as would be possible with a side chain of one of the amino acids.
  • the C-carbon atom is the carbonyl carbon atom of the N-terminal amino acid of the peptide.
  • This embodiment is particularly preferred because the peptide immediately after the on ⁇ bring the 11 C-labeled amino acid can be used.
  • ⁇ C-carbon has a half-life of only about 20 Minu ⁇ th, so that the radiation dose must be chosen higher, is the more time between the synthesis of the peptide and sides ner use. If the 11 C-labeling with the N-terminal amino acid and thus in the last step of the synthesis is applied, the peptide can be used immediately after its synthesis.
  • the time Zvi ⁇ rule the processing of ⁇ C-carbon and the use of the peptide is reduced so that the radiation loss during the preparation of the peptide is minimized. Therefore, the radiation dose that must be used in the processing of the 11 C carbon to ensure a certain radiation intensity of the product, be correspondingly lower.
  • the production is more cost-effective and thereby the radiation exposure for the technical staff that forth ⁇ represents the peptide reduced.
  • the peptide has at least one D-amino acid. With the exception of glycine, all amino acids have a chiral center at their alpha carbon atom and can therefore exist as configurational isomers, namely as the D or L amino acid. Endogenous peptides and proteins are largely composed of amino acids in L configuration. In addition, most natural proteases and peptidases work stereoselectively and
  • Another possible ⁇ ness, to influence the pharmacological clearance of the peptide, is to replace individual amino acids of the peptide by unnatural amino acids with similar chemical properties.
  • the non-natural amino acids are metabolized more slowly because the body's own proteolytic enzymes are specifically involved in the breakdown of natural amines. Nocicren are adjusted.
  • the unnatural amino acids should be chosen, however, that the binding affinity of the peptide is not changed ⁇ changed.
  • other chemical modifications of individual amino acids of the peptide are possible in order to obtain the
  • Example ⁇ as can be Replace the terminal amino group of the peptide by a isonitrile. Such modification redu ⁇ the sheet, conveyed from the amino group, interaction with proteolytic enzymes without altering the bond between the peptide used in the invention and the antibody.
  • Another object of the invention is a radiopharmaceutical for the localization of a diseased tissue comprising a peptide having an 11 C carbon atom.
  • the amino acid sequence of the peptide originates from the amino acid sequence of Pro ⁇ teins from which is formed by the pathological tissue, and the peptide binds to a human leukocyte antigen (HLA) complex, which is also formed from the diseased tissue.
  • HLA human leukocyte antigen
  • the radiopharmaceutical is administered to the patient, and the peptides contained therein are rapidly and efficiently distributed in the body because of their size.
  • You'm ⁇ according to the chemical equilibrium with the zellei ⁇ antigenic peptide to the HLA complex of the diseased tissue and accumulate on the surface.
  • This tissue can at ⁇ play, a focus of inflammation by viruses or bacteria be infected cells or a tumor.
  • the accumulation of radioactively labeled peptides is detected by positron emission tomography (PET), which determines the exact position of the infected cells, the inflammation or the tumor in the patient's body.
  • PET positron emission tomography
  • the peptide used according to the invention is selected so that its amino acid sequence is derived from a specific, naturally formed protein.
  • the peptide then binds to the cells that make up this protein because the cells present corresponding HLA complexes on their surface.
  • Markie ⁇ tion of the peptide with a C-11 carbon atom (PET) can be shown by means of positron emission tomography to which cells of the body, the peptide has bound.
  • the 11 C-carbon atom is a carbonyl carbon atom of an amino acid, preferably the carbonyl carbon atom of the N-terminal amino acid of the peptide.
  • the radiopharmaceutical is a PET biomarker.
  • PET is an established method for detecting the radiation of radioactive elements and determining their position (Massoud TF, Gambhir SS, 2003). With the aid of detector devices arranged annularly around the patient, sectional images are created on which the decay events in their spatial distribution in the interior of the body are represented. The PET also makes it possible to determine the amount of mar ⁇ -labeled molecules quantitatively in a tissue.
  • a method for localizing a diseased tissue in an organism comprising Steps a) providing a peptide, b) administering the peptide to the organism, c) detecting the peptide in the organism by positron emission tomography (PET).
  • PET positron emission tomography
  • the amino acid sequence of the peptide is derived from the amino acid sequence of a protein formed by the diseased tissue and the peptide binds to a human leukocyte antigen (HLA) complex formed by the diseased tissue.
  • HLA human leukocyte antigen
  • the peptide has an 11 C carbon atom.
  • the peptide used in the invention is an HLA Kom ⁇ plex is detected inside an organism, and isolated, so that the distribution of HLA complex may be observed in the body of a Pati ⁇ ducks. In this way, for example, the size or extent of an infection or a
  • Tumors are determined.
  • the peptide used according to the invention is therefore outstandingly suitable for observing the course and success of a treatment, so-called therapy monitoring.
  • FIG. 1 shows schematically the binding between a peptide 1 and a human leukocyte antigen (HLA) complex 4, which is arranged on the surface of a diseased tissue 18.
  • HLA human leukocyte antigen
  • Peptide 1 comprises nine amino acids 2, of which the N-terminal amino acid 3 is radioactively labeled with an 11 C carbon atom.
  • the radioactive label is represented by an asterisk (*).
  • the peptide 1 is arranged in the peptide binding site 5 of the HLA complex 4.
  • the peptide binding site 5 is formed from two highly variable domains, whereby a specific affinity between the HLA complex 4 and the peptide 1 arises.
  • the HLA complex 4 is an integra ⁇ les membrane protein that extends through a cell membrane 6 of the cells of the diseased tissue 18 therethrough. It has an extracellular 7 and an intracellular 8 area.
  • the peptide binding site is at the 5 extrazellulä ⁇ ren region 7 of the HLA complex 4.
  • the membrane 6 is shown gray shaded.
  • the 11 C-labeled peptide 1 binds specifically to the free
  • the peptide 1 can be used to detect the HLA Kom ⁇ plexes 4 by the positrons emitted at the decay of the X1 C carbon atoms are detected by positron emission tomography (PET). The location of the positron emission corresponding to the location of the peptide 1 and the bound thereto HLA complex 4. Makes a pathological Ge ⁇ weave 18 the HLA complex 4, it can be detek- advantage by the peptide. 1
  • a diseased tissue 18 for example of a tumor as part of a diagnosis of cancer is administered to a Pati ⁇ ducks a radiopharmaceutical containing the d e ⁇ labeled peptide.
  • Peptide 1 binds specifically to HLA complex 4, which is formed by the cells of tumor 18. Since the peptide 1 ⁇ by accumulates at the tumor 18.
  • HLA complex 4 Since the peptide 1 ⁇ by accumulates at the tumor 18.
  • Anou ⁇ Fung is visualized by PET and so the distribution of HLA complex 4 or the position of the tumor 18 in the body of the patient determined. In this way, newly formed metastases, which form the HLA complex 4, can be detected using PET.
  • the information obtained by the visualization of the tumor 18 may serve to medicate a tumor therapeutic, for example, amount of drug and Administration schedule to adjust according to the position, size and distribution of the tumor 18.
  • FIG. 2 shows a representation of a peptide 1 by means of a chemical formula.
  • Peptide 1 comprises nine amino acids 2 of the following sequence: glycine-valine-leucine-proline-alanine-leucine-proline-glutamine-valine.
  • the N-terminal glycine is by structural formula represents ⁇ Darge, the following amino acids 2 by their respective three-letter code.
  • the sequence of the peptide is also given in SEQ ID NO: 1.
  • the carbonyl carbon atom of the N-terminal glycine is an 11 C carbon atom represented by the number 11 above the carbonyl carbon atom.
  • Peptide 1 is prepared by conventional protein synthesis methods and the 11 C-labeled N-terminal amino acid 3 is added in the last step, because the half-life of the X1 carbon carbon isotope is only about 20 minutes.
  • peptide synthesis with the 11 C-labeled amino acid is submitschlos ⁇ sen that Peptide 1 can be used immediately after labeling.
  • the peptide of the sequence SEQ ID NO: 1 is derived from the human glycoprotein chorionic gonadotropin (hCG-beta) (SEQ ID NO: 2), which fulfills the functions of a hormone during pregnancy. It influences the development of the embryo, in particular the differentiation of trophoblasts and embryonic blood vessel formation. In addition, however, hCG-beta is also produced by cells of various tumor types, such as breast, liver and lung tumors. The hCG-beta is degraded by the tumor cells into shorter peptides and in Form of complexes of HLA and hCG-beta peptides presented on the cell surface.
  • hCG-beta human glycoprotein chorionic gonadotropin
  • the peptide of the SEQ ID No .: 1 in the peptide binding site 5 of the HLA complex is 4 ge ⁇ prevented and the overall complex on the cell membrane of the tumor cells anchored.
  • HLA complexes 4 having a specific affinity for the peptide of SEQ ID NO: 1 are located on the tumor 18 so that it can be detected with the 11 C-labeled peptide of SEQ ID NO: 1.
  • Figure 3 shows a schematic representation (greatly simplified by Faller A, Schünke M, The Human Body, Thieme, 2008) of a circulatory system 10 of an organism and the distribution of a peptide 1 therein.
  • the circulation system 10 includes various organs schematically represented, such as the lungs 12, heart 13, liver 14, 15 intestine and kidney 16 and the main wires 11 which these organs ver ⁇ bind.
  • the peptide 1 is represented by triangles along the wires 11.
  • the degradation products 17 of the peptide 1 are represented by individual lines within the outline of the kidney 16 Darge ⁇ .
  • Left of center of the circulatory system 10 is additionally ⁇ a diseased tissue 18, for example, a tumor or an inflammation, shown, the HLA complexes 4 carries are in turn attached to the peptides. 1
  • the distribution of the peptide 1 in the circulatory system 10 comprises four phases, which are listed along the top-down view.
  • Phase I Peptide 1 is injected into the circulatory system 10 of the organism.
  • Phase II is via the blood circulatory system 10 Peptide 1 in the organs 12, 13, 14, 15, and 16 of the body transported ⁇ advantage.
  • Phase III The circulating peptide 1 specifically binds to the HLA complexes 4, and accumulates at the morbid tissue ⁇ be 18 because this is the HLA complex. 4
  • Phase IV Unbound peptide 1 is rapidly metabolised and enzymatically degraded.
  • the organism not failed ⁇ det between own peptides and the peptide 1, because it is composed of amino acids 2, 3, which correspond to the body's own molecules.
  • the degradation products 17 of the peptide of amino acids 1 and 2, 3 collect predominantly they are over the bladder and the ureter excreted ⁇ in the kidney 16 from where.
  • Massoud TF, Gambhir SS Molecular imaging in living subjects: seeing fundamental biological processes in a new light; Genes Dev. 2003 Mar 1; 17 (5): 545-80.

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Abstract

L'invention concerne l'utilisation d'un peptide (1) pour la production d'un agent destiné à la détection d'un tissu malade (18). La séquence d'acides aminés du peptide (1) provient de la séquence d'acides aminés d'une protéine formée par le tissu malade (18) et le peptide (1) se lie à un complexe d'antigènes des leucocytes humains (HLA) (4) également formé par le tissu malade (18). Le peptide (1) comprend en outre un atome de carbone 11C. L'invention porte également sur un radiopharmaceutique destiné à la localisation d'un tissu malade (18) qui comporte un tel peptide (1).
PCT/EP2011/060424 2010-06-30 2011-06-22 Peptide marqué 11c pour la détection d'un tissu malade WO2012000862A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE201010026063 DE102010026063A1 (de) 2010-06-30 2010-06-30 11C-markiertes Peptid zur Detektion eines krankhaften Gewebes
DE102010026063.0 2010-06-30

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Citations (5)

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WO2001083693A2 (fr) * 2000-04-28 2001-11-08 Glaxo Group Limited Composes ayant une affinite pour le recepteur 2 du facteur de croissance de l'endothelium vasculaire (vegfr-2) et utilisations associees
WO2004085461A2 (fr) 2003-03-24 2004-10-07 Immatics Biotechnologies Gmbh Peptide associe a une tumeur et se liant a des molecules mhc
WO2006017619A2 (fr) * 2004-08-06 2006-02-16 The Regents Of The University Of California Peptides cycliques de liaison a un recepteur et leurs methodes d'utilisation
DE102009035645A1 (de) 2009-07-29 2011-02-03 Siemens Aktiengesellschaft Verfahren zur Herstellung eines radioaktiv markiertren Peptids
DE102009035648B3 (de) 2009-07-29 2011-03-17 Siemens Aktiengesellschaft Verfahren zur Herstellung eines radioaktiv markierten Carboxylats sowie die Verwendung einer Mikroelektrode zur elektrochemischen Synthese eines radioaktiv markierten Carboxylats

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CN102174108B (zh) * 2002-03-01 2016-06-29 免疫医疗公司 内在化抗-cd74抗体和使用方法
WO2009045579A2 (fr) * 2007-06-14 2009-04-09 The Regents Of The University Of California Sondes d'imagerie multimodes pour imagerie et thérapie in vivo ciblées et non ciblées

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WO2001083693A2 (fr) * 2000-04-28 2001-11-08 Glaxo Group Limited Composes ayant une affinite pour le recepteur 2 du facteur de croissance de l'endothelium vasculaire (vegfr-2) et utilisations associees
WO2004085461A2 (fr) 2003-03-24 2004-10-07 Immatics Biotechnologies Gmbh Peptide associe a une tumeur et se liant a des molecules mhc
WO2006017619A2 (fr) * 2004-08-06 2006-02-16 The Regents Of The University Of California Peptides cycliques de liaison a un recepteur et leurs methodes d'utilisation
DE102009035645A1 (de) 2009-07-29 2011-02-03 Siemens Aktiengesellschaft Verfahren zur Herstellung eines radioaktiv markiertren Peptids
DE102009035648B3 (de) 2009-07-29 2011-03-17 Siemens Aktiengesellschaft Verfahren zur Herstellung eines radioaktiv markierten Carboxylats sowie die Verwendung einer Mikroelektrode zur elektrochemischen Synthese eines radioaktiv markierten Carboxylats

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FALLER A, SCHÜNKE M: "Der Körper des Menschen", 2008, THIEME-VERLAG
HARTVIG P ET AL: "Kinetics of four <11>C-labelled enkephalin peptides in the brain, pituitary and plasma of Rhesus monkeys", REGULATORY PEPTIDES, ELSEVIER SCIENCE BV, NL, vol. 16, no. 1, 1 December 1986 (1986-12-01), pages 1 - 13, XP023462538, ISSN: 0167-0115, [retrieved on 19861201], DOI: 10.1016/0167-0115(86)90190-4 *
HENRIKSEN G ET AL: "Proof of principle for the use of 11C-labelled peptides in tumour diagnosis with PET", EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, SPRINGER VERLAG, HEIDELBERG, DE, vol. 31, no. 12, 10 August 2004 (2004-08-10), pages 1653 - 1657, XP002383248, ISSN: 1619-7070, DOI: 10.1007/S00259-004-1582-1 *
HISS JA, BREDENBECK A, LOSCH FO, WREDE P, WALDEN P, SCHNEIDER G: "Design of MHC I stabilizing peptides by agent-based exploration of sequence space", PROTEIN ENG DES SEL., vol. 20, no. 3, March 2007 (2007-03-01), pages 99 - 108
MASSOUD TF, GAMBHIR SS: "Molecular imaging in living subjects: seeing fundamental biological processes in a new light", GENES DEV., vol. 17, no. 5, 1 March 2003 (2003-03-01), pages 545 - 80, XP007905304, DOI: doi:10.1101/gad.1047403
NEUNDORF I, RENNERT R, FRANKE J, KÖZLE I, BERGMANN R: "Detailed analysis concerning the biodistribution and metabolism of human calcitonin-derived cell-penetrating peptides", BIOCONJUG CHEM., vol. 19, no. 8, August 2008 (2008-08-01), pages 1596 - 603, XP002575961, DOI: doi:10.1021/bc800149f
WALSHE VA, HATTOTUWAGAMA CK, DOYTCHINOVA IA, WONG M, MACDONALD IK, MULDER A, CLAAS FH, PELLEGRINO P, TURNER J, WILLIAMS I: "Integrating in silico and in vitro analysis of peptide binding affinity to HLA Cw*0102: a bioinformatic approach to the prediction of new epitopes", PLOS ONE, vol. 4, no. 11, 30 November 2009 (2009-11-30), pages E8095

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