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WO1999000150A9 - Ciblage d'un medicament radiopharmaceutique peptidique utilisant in vivo la barriere hemato-encephalique d'un primate et un anticorps monoclonal dirige contre le recepteur humain de l'insuline - Google Patents

Ciblage d'un medicament radiopharmaceutique peptidique utilisant in vivo la barriere hemato-encephalique d'un primate et un anticorps monoclonal dirige contre le recepteur humain de l'insuline

Info

Publication number
WO1999000150A9
WO1999000150A9 PCT/US1998/013398 US9813398W WO9900150A9 WO 1999000150 A9 WO1999000150 A9 WO 1999000150A9 US 9813398 W US9813398 W US 9813398W WO 9900150 A9 WO9900150 A9 WO 9900150A9
Authority
WO
WIPO (PCT)
Prior art keywords
brain
radiolabeled
peptide
composition
monoclonal antibody
Prior art date
Application number
PCT/US1998/013398
Other languages
English (en)
Other versions
WO1999000150A2 (fr
WO1999000150A3 (fr
Inventor
William M Pardridge
Original Assignee
Univ California
William M Pardridge
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 Univ California, William M Pardridge filed Critical Univ California
Priority to AU82698/98A priority Critical patent/AU8269898A/en
Publication of WO1999000150A2 publication Critical patent/WO1999000150A2/fr
Publication of WO1999000150A3 publication Critical patent/WO1999000150A3/fr
Publication of WO1999000150A9 publication Critical patent/WO1999000150A9/fr

Links

Classifications

    • 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
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies

Definitions

  • the present invention relates generally to the introduction of radiolabeled peptide pharmaceutical agents into the brain by transcytosis across the blood-brain barrier.
  • Peptide radiopharmacueticals have potential for diagnostic imaging.
  • the somatostatin receptor is overexpressed in certain neuroendocrine tumors, as well as brain tumors, such as meningiomas or gliomas and [ I]- or [ In]-labeled octreotide, a somatostatin peptide analog, has been used to image these tumors.
  • octreotide Owing to the small size of the peptide radiopharmaceutical, octreotide readily crosses the porous capillaries perfusing tumors in the periphery, or certain brain tumors, such as meningiomas, which lack a blood-brain barrier (BBB).
  • BBB blood-brain barrier
  • gliomas which also overexpress somatostatin receptors, have an intact BBB, and it is not possible to image these tumors with octreotide, since this peptide does not cross the BBB in vivo.
  • the A ⁇ amyloid of tissue sections of AD autopsy brain can be identified with dyes, such as
  • FIG 11 Scheme depicting the multifunctionality and three domains of the peptide radiopharmaceutical conjugated to the blood-brain barrier (BBB) delivery system
  • the imaging agent is comprised of amyloid binding domain, a linker domain, and a
  • the 8314/SA A- 280 peak ( Figure 1A) was greater than the 8314/SA 3 H-biotin binding peak ( Figure IB), which indicated unconjugated 83-14 MAb was also contained in this peak.
  • K D 0.45 nM
  • unconjugated 83-14 MAb could compete for binding to the BBB of the 8314/SA conjugate. Therefore, unconjugated 83-14 MAb was removed by iminobiotin affinity chromatography. The fractions from the Sephacryl S-300 column were concentrated with a Centricon-30 (Amicon Inc., Beverly, MA).
  • reaction solution was diluted with 1 mL of 90% acetonitrile/ 10% 20 mM TEAP (trimethylamine/phosphoric acid)/pH 2.8 and loaded onto the PHEA extraction cartridge, which was pre-activated with 5 mL of 90% acetonitrile as shown in Figure 2.
  • the plasma TCA-precipitable radioactivity date was subjected to a biexponential analysis to compute the pharmacokinetic parameters shown in Table 1
  • the frontal cortex was counted for total [ 125 I] radioactivity, and the brain volume of distribution (V D ) was computed for the A ⁇ 1" 40 with or without conjugation to the 83 14/DA vector.
  • the gray matter BBB permeability-surface area (PS) for the free peptide or for the conjugate was computed from the brain V D and the plasma area under the concentration curve (AUC), and was ⁇ 0.25 and 1 74 ⁇ L/min g, respectively.
  • the synthesis and purification of the 8314/SA vector requires a two-step procedure involving Sephacryl S-300 gel filtration ( Figure 1), and iminobiotin affinity chromatography ( Figure 2)
  • the first chromatographic procedure removes unconjugated streptavidin
  • the second chromatography removes unconjugated 83-14 MAb
  • the use of the iminobiotin affinity chromatography is a novel procedure that allows for elution of the 8314/SA conjugate from the iminobiotin column under relatively mild conditions It is imperative to remove all unconjugated 83-14 MAb, because the affinity of this antibody for the BBB insulin receptor is extremely high with a K D of 0 45 ⁇ 0 10 nM 921) Therefore, the presence of any unconjugated 83-14 MAb in the formulation comprised of the 83 14/SA complex would compete with binding of the 8314/SA conjugate to the BBB insulin receptor, and this would inhibit brain uptake of the conjugated peptide radiopharmac

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Optics & Photonics (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Physics & Mathematics (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

Selon cette invention, le peptide [125I]-Aβ1-40 a été mono-biotinylé et conjugué à un système de ciblage cérébral et d'administration d'un médicament à la barrière hémato-encéphalique (BBB), système renfermant un complexe de l'anticorps monoclonal 83-14 (MAb) dirigé contre le récepteur humain de l'insuline et marqué par la streptavidine (SA) et ce, dans le but de produire, trois heures après l'injection intraveineuse, un accroissement sensible de l'assimilation du [125I]-bio-Aβ1-40 par le cerveau du singe rhésus, par rapport à l'assimilation obtenue sans administration de médicament à la BBB.
PCT/US1998/013398 1997-06-27 1998-06-26 Ciblage d'un medicament radiopharmaceutique peptidique utilisant in vivo la barriere hemato-encephalique d'un primate et un anticorps monoclonal dirige contre le recepteur humain de l'insuline WO1999000150A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU82698/98A AU8269898A (en) 1997-06-27 1998-06-26 Drug targeting of a peptide radiopharmaceutical through the primate blood-brain barrier in vivo with a monoclonal antibody to the human insulin receptor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US5106597P 1997-06-27 1997-06-27
US60/051,065 1997-06-27

Publications (3)

Publication Number Publication Date
WO1999000150A2 WO1999000150A2 (fr) 1999-01-07
WO1999000150A3 WO1999000150A3 (fr) 1999-04-01
WO1999000150A9 true WO1999000150A9 (fr) 1999-05-14

Family

ID=21969115

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/013398 WO1999000150A2 (fr) 1997-06-27 1998-06-26 Ciblage d'un medicament radiopharmaceutique peptidique utilisant in vivo la barriere hemato-encephalique d'un primate et un anticorps monoclonal dirige contre le recepteur humain de l'insuline

Country Status (2)

Country Link
AU (1) AU8269898A (fr)
WO (1) WO1999000150A2 (fr)

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WO1999000150A2 (fr) 1999-01-07
WO1999000150A3 (fr) 1999-04-01
AU8269898A (en) 1999-01-19

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