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Publication Number
US-11028155-B2
Publication Date
2021-06-08
Expiration Date
Abstract
Compositions and methods related to antibodies or antibody fragments which are capable of crossing the blood brain barrier are provided.
Core Innovation
The invention provides recombinant antigen binding proteins, including an antibody comprising a heavy chain and a light chain. The heavy chain comprises a heavy chain acceptor framework of SEQ ID NO: 1, and the light chain comprises a light chain acceptor framework of SEQ ID NO: 2, with heterologous CDRs grafted into the acceptor frameworks to generate CDR-swapped or re-engineered antibodies.
The disclosure provides CDR grafting using CDR1, CDR2 and CDR3 segments. The light chain CDR1, CDR2 and CDR3 at amino acids 28-34, 50-56 and 91-97 of SEQ ID NO:2 are replaced with the CDR1, CDR2 and CDR3 at amino acids 148-152, 170-172 and 208-216 of SEQ ID NO:4, respectively, and the heavy chain CDR1, CDR2 and CDR3 at amino acids 31-35, 50-59 and 101-109 of SEQ ID NO:1 are replaced with the CDR1, CDR2 and CDR3 at amino acids 26-33, 51-58 and 97-110 of SEQ ID NO:4, respectively.
The document links the antibody architecture to pritumumab and states that pritumumab crosses the blood-brain barrier. It also describes use of the human IgG1 framework of pritumumab as an acceptor framework for CDR swapping, and states that the recombinant antigen binding proteins can be provided in multiple antibody formats, including whole immunoglobulin, scFv, Fab, F(ab’)2, Fv, nanobody, and bispecific antibody formats.
Claims Coverage
The independent claim covers one inventive feature centered on an antibody structure defined by heavy-chain and light-chain acceptor frameworks with specified CDR replacements. The claim set further includes blood-brain barrier crossing, a pharmaceutical composition with a pharmaceutically acceptable carrier, and formulation for delivery to the brain, for a total of four inventive features.
CDR-swapped antibody with specified acceptor frameworks
An antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain acceptor framework of SEQ ID NO: 1 and the light chain comprises a light chain acceptor framework of SEQ ID NO: 2, with the light chain CDR1, CDR2 and CDR3 and the heavy chain CDR1, CDR2 and CDR3 replaced with CDRs from SEQ ID NO: 4 at the specified amino-acid positions.
Antibody capable of crossing the blood-brain barrier
The antibody is capable of crossing the blood-brain barrier.
Pharmaceutical composition including the antibody and pharmaceutically acceptable carrier
A pharmaceutical composition that includes the antibody together with a pharmaceutically acceptable carrier.
Composition formulated for delivery to the brain
The composition is formulated for delivery to the brain.
Overall, the claims center on a CDR-replacement antibody defined by heavy- and light-chain acceptor frameworks and specific CDR replacements from SEQ ID NO: 4. The coverage is further narrowed by functional blood-brain barrier crossing and by pharmaceutical composition context and brain-delivery formulation.
Stated Advantages
Enables crossing the blood-brain barrier.
Supports use as a delivery vehicle for brain delivery.
Provides targeting or localization to brain tumor tissue versus normal brain.
Allows conjugation to therapeutic moieties or imaging agents.
Documented Applications
Therapeutic delivery across the blood-brain barrier.
Treating cancer and other diseases.
Treating cancer.
Treating infectious disease.
Treating autoimmune disorders.
Addressing transplantation rejection.
Brain delivery using pritumumab as a delivery vehicle that crosses the blood-brain barrier, including optional conjugation to therapeutic moieties or imaging agents.
Assessment of binding specificity across tissues, including localization to brain tumor tissue versus normal brain.
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