Anti-transferrin receptor antibody and antibody-drug conjugates cross the blood-brain barrier

Journal Article · Sat Jun 01 00:00:00 EDT 1991 · Proceedings of the National Academy of Sciences of the United States of America; (United States)

DOI:https://doi.org/10.1073/pnas.88.11.4771· OSTI ID:5509622

Friden, P M; Walus, L R; Musso, G F; Taylor, M A; Malfroy, B; Starzyk, R M ^[1]

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1. Alkermes, Inc., Cambridge, MA (USA)

Delivery of nonlipophilic drugs to the brain is hindered by the tightly apposed capillary endothelial cells that make up the blood-brain barrier. The authors have examined the ability of a monoclonal antibody (OX-26), which recognizes the rat transferrin receptor, to function as a carrier for the delivery of drugs across the blood-brain barrier. This antibody, which was previously shown to bind preferentially to capillary endothelial cells in the brain after intravenous administration, labels the entire cerebrovascular bed in a dose-dependent manner. The initially uniform labeling of brain capillaries becomes extremely punctate {approximately} 4 hr after injection, suggesting a time-dependent sequestering of the antibody. Capillary-depletion experiments, in which the brain is separated into capillary and parenchymal fractions, show a time-dependent migration of radiolabeled antibody from the capillaries into the brain parenchyma, which is consistent with the transcytosis of compounds across the blood-brain barrier. Antibody-methotrexate conjugates were tested in vivo to assess the carrier ability of this antibody. Immunohistochemical staining for either component of an OX-26-methotrexate conjugate revealed patterns of cerebrovascular labeling identical to those observed with the unaltered antibody. Accumulation of radiolabeled methotrexate in the brain parenchyma is greatly enhanced when the drug is conjugated to OX-26.

• OSTI ID: 5509622
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (United States), Vol. 88:11; ISSN 0027-8424
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
BLOOD-BRAIN BARRIER
PERMEABILITY
DRUGS
MEMBRANE TRANSPORT
MONOCLONAL ANTIBODIES
BIOLOGICAL FUNCTIONS
TRANSFERRIN
RECEPTORS
AUTORADIOGRAPHY
BRAIN
CAPILLARIES
DOSE-RESPONSE RELATIONSHIPS
ENDOTHELIUM
METHOTREXATE
RATS
TIME DEPENDENCE
TRITIUM COMPOUNDS
ANIMAL TISSUES
ANIMALS
ANTIBODIES
ANTIMETABOLITES
BLOOD VESSELS
BODY
CARDIOVASCULAR SYSTEM
CENTRAL NERVOUS SYSTEM
GLOBULINS
GLOBULINS-BETA
HYDROGEN COMPOUNDS
MAMMALS
MEMBRANE PROTEINS
METALLOPROTEINS
NERVOUS SYSTEM
ORGANIC COMPOUNDS
ORGANS
PROTEINS
RODENTS
TISSUES
VERTEBRATES
550201* - Biochemistry- Tracer Techniques