Targeted delivery of anti-CSF1R antibodies to joints with tenosynovial giant cell tumors
Inventors
Alani, Laman • Johnson, Kirk William • Huang, Michael • Hsu, Chung-Chiang
Assignees
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Publication Number
US-11752096-B2
Publication Date
2023-09-12
Expiration Date
Abstract
The present disclosure provides compositions and methods for intra-articular delivery of anti-CSF1R antibodies to a tissue that is impacted by a disease that is treatable with CSF1/CSF1R inhibition and/or that expresses CSF1R. It was conventional knowledge that the intra-articular dwell time of proteins in joints is typically a few hours or less. The present disclosure shows, however, that intra-articular delivery of an anti-CSF1R antibody can lead to sustained exposure and pharmacologic activity of the antibody in the joints far beyond a few hours, providing an effective means for targeted and extended delivery of the therapeutic agent.
Core Innovation
The invention provides methods for administering an anti-CSF1R antibody to a mammalian subject using local administration of a composition comprising the antibody at or proximate to a tissue. The tissue is a joint impacted with tenosynovial giant cell tumor (TGCT) and includes at least a cell that expresses CSF1R on the surface.
The approach focuses on local delivery to joints and supports sustained synovial residence and pharmacologic activity weeks after dosing, contrasting with conventional short protein joint dwell times and reduced serum exposure. The locally administered anti-CSF1R antibody is associated with local CSF1R inhibition indicated by CSF1 changes and with sustained tissue-level synovial drug levels.
TGCT patient trial findings are used to support the method, including objective tumor responses by MRI using RECIST v1.1 and modified RECIST, and improvements in pain and range of motion. The document further describes nonclinical intra-articular (IA) PK/toxicology in cynomolgus monkeys and a clinical safety/PK overview, together with formulation approaches intended to enable controlled/sustained local release, including thermogels and biodegradable matrices, as well as polymer excipients.
Claims Coverage
The document contains two independent claims covering local administration of an anti-CSF1R antibody to a CSF1R-expressing TGCT-impacted joint tissue in a mammalian subject, and treating TGCT at a joint in a patient by administering an anti-CSF1R antibody at or proximate to the TGCT. Across the dependent claims, the coverage adds multiple inventive feature options including specific antibody identities, administration at intra-articular/intra-tumoral locations, dose threshold constraints, dosing interval constraints, sustained exposure duration options, and specified polymer excipients for local compositions.
Local administration of anti-CSF1R antibody to a TGCT-impacted joint tissue expressing CSF1R
A method administers an anti-CSF1R antibody by local administration of a composition comprising the antibody at or proximate to a joint impacted with tenosynovial giant cell tumor (TGCT), where the tissue comprises at least a cell that expresses CSF1R on the surface.
Treating TGCT at a joint by administering an anti-CSF1R antibody at or proximate to the TGCT
A method for treating tenosynovial giant cell tumor (TGCT) at a joint in a patient, comprising administering an anti-CSF1R antibody at or proximate to the TGCT at the joint in the patient.
Overall, the claims cover local delivery of anti-CSF1R antibody compositions to TGCT-impacted joint tissues with CSF1R-expressing cells, and treating TGCT at the joint in a patient by administering an anti-CSF1R antibody at or proximate to the TGCT, with dependent claims narrowing to particular antibodies, administration location, dosing and interval constraints, and specified polymer excipients.
Stated Advantages
Sustained synovial residence and pharmacologic activity weeks after dosing.
Reduced serum exposure.
Objective tumor responses by MRI using RECIST v1.1 and modified RECIST.
Improved pain and range of motion.
Local CSF1R inhibition indicated by CSF1 increases and sustained synovial drug levels.
Clinical safety and PK overview is provided for the approach.
Documented Applications
Administration of anti-CSF1R antibodies to TGCT-impacted joints using local administration at or proximate to joint tissue, including intra-articular and proximate/intra-tumoral delivery.
Treating tenosynovial giant cell tumor (TGCT) at a joint in a patient by administering an anti-CSF1R antibody at or proximate to the TGCT at the joint.
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