초록 ▼

The blood-brain barrier (BBB) prevents transport of molecules larger than 500 Dal tons from blood to brain. Receptor-mediated transcytosis (RMT) facilitates transport across the BBB of specific molecules that bind receptors on brain endothelial cells that form the BBB. An insulin-like growth factor

The blood-brain barrier (BBB) prevents transport of molecules larger than 500 Dal tons from blood to brain. Receptor-mediated transcytosis (RMT) facilitates transport across the BBB of specific molecules that bind receptors on brain endothelial cells that form the BBB. An insulin-like growth factor 1 receptor (IGF 1R)-binding antibody or fragment thereof is identified that transmigrates the BBB by RMT. The antibody or fragment is used to deliver a cargo molecule across the BBB, wherein the cargo molecule may be a therapeutic or detectable agent. The antibody is a camelid VHH, prepared by immunizing a llama with a 933-amino acid IGF 1R polypeptide. Humanized forms of the camelid VHH are also generated.

대표청구항 ▼

1. An isolated or purified single domain antibody or antigen-binding fragment thereof, comprising a complementarity determining region (CDR) 1 sequence of GRTIDNYA (SEQ ID NO:1);a CDR2 sequence of IDWGDGGX (SEQ ID NO:2), where X is A or T; anda CDR3 sequence of AMARQSRVNLDVARYDY (SEQ ID NO:3),wherei

1. An isolated or purified single domain antibody or antigen-binding fragment thereof, comprising a complementarity determining region (CDR) 1 sequence of GRTIDNYA (SEQ ID NO:1);a CDR2 sequence of IDWGDGGX (SEQ ID NO:2), where X is A or T; anda CDR3 sequence of AMARQSRVNLDVARYDY (SEQ ID NO:3),wherein the single domain antibody or antigen-binding fragment thereof specifically binds the Insulin-Like Growth Factor 1 Receptor (IGF1R). 2. The isolated or purified single domain antibody or antigen-binding fragment thereof of claim 1, comprising the sequence X1VX2LX3ESGGGLVQX4GGSLRLSCAASGRTIDNYAMAWX5RQAPGKX6X7EX8V X9TIDWGDGGX10RYANSVKGRFTISRDNX11KX12TX13YLQMNX14LX15X16EDTAV YX17CAMARQSRVNLDVARYDYWGQGTX18VTVSS (SEQ ID NO:4), where X1 is E or Q; X2 is K or Q; X3 is V or E; X4 is A or P; X5 is V or S; X6 is D or G; X7 is L or R; X8 is F or W; X9 is A or S; X10 is A or T; X11 is A or S; X12 is G or N; X13 is M or L; X14 is N or R; X15 is E or R; X16 is P or A; X17 is S or Y; and X18 is Q or L. 3. The isolated or purified single domain antibody or antigen-binding fragment thereof of claim 1, comprising a sequence selected from the group consisting of: (SEQ ID NO: 5)QVKLEESGGGLVQAGGSLRLSCAASGRTIDNYAMAWSRQAPGKDREFVATIDWGDGGARYANSVKGRFTISRDNAKGTMYLQMNNLEPEDTAVYSCAMARQSRVNLDVARYDYWGQGTQVTVSS;(SEQ ID NO: 6)EVQLVESGGGLVQPGGSLRLSCAASGRTIDNYAMAWVRQAPGKGLEWVSTIDWGDGGTRYANSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAMARQSRVNLDVARYDYWGQGTLVTVSS;(SEQ ID NO: 7)QVQLVESGGGLVQPGGSLRLSCAASGRTIDNYAMAWVRQAPGKGLEWVATIDWGDGGTRYANSVKGRFTISRDNSKNTMYLQMNSLRAEDTAVYYCAMARQSRVNLDVARYDYWGQGTLVTVSS;(SEQ ID NO: 8)QVQLVESGGGLVQPGGSLRLSCAASGRTIDNYAMAWSRQAPGKGLEFVATIDWGDGGTRYANSVKGRFTISRDNSKNTMYLQMNSLRAEDTAVYYCAMARQSRVNLDVARYDYWGQGTLVTVSS;(SEQ ID NO: 9)QVQLVESGGGLVQPGGSLRLSCAASGRTIDNYAMAWSRQAPGKDREFVATIDWGDGGTRYANSVKGRFTISRDNSKGTMYLQMNSLRAEDTAVYSCAMARQSRVNLDVARYDYWGQGTLVTVSS; and(SEQ ID NO: 10)EVQLVESGGGLVQPGGSLRLSCAASGRTIDNYAMAWSRQAPGKDREFVSTIDWGDGGTRYANSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAMARQSRVNLDVARYDYWGQGTLVTVSS. 4. The isolated or purified single domain antibody or antigen-binding fragment thereof of claim 1, wherein the single domain antibody is of camelid origin. 5. The isolated or purified single domain antibody or antigen-binding fragment thereof of claim 1, wherein the single domain antibody or antigen-binding antibody fragment thereof is in a multivalent display format. 6. The isolated or purified single domain antibody or antigen-binding fragment thereof of claim 5, wherein the single domain antibody or antigen-binding fragment thereof is linked to a Fc fragment. 7. The isolated or purified single domain antibody or antigen-binding fragment thereof of claim 1, wherein the single domain antibody or antigen-binding fragment thereof is immobilized onto a surface. 8. The isolated or purified single domain antibody or antigen-binding fragment thereof of claim 1, wherein the single domain antibody or antigen-binding fragment thereof is linked to a cargo molecule. 9. The isolated or purified single domain antibody or antigen-binding fragment thereof of claim 8, wherein the cargo molecule has a molecular weight in the range of about 1 kD to about 200 kDa. 10. The isolated or purified single domain antibody or antigen-binding fragment thereof of claim 8, wherein the cargo molecule is a detectable agent, a therapeutic, a peptide, a growth factor, a cytokine, a receptor trap, a chemical compound, a carbohydrate moiety, an enzyme, an antibody or fragment thereof, a DNA-based molecule, a viral vector, or a cytotoxic agent; one or more liposomes or nanocarriers loaded with a detectable agent, a therapeutic, a peptide, an enzyme, an antibody or fragment thereof, a DNA-based molecule, a viral vector, or a cytotoxic agent; or one or more nanoparticle, nanowire, nanotube, or quantum dots. 11. A composition comprising one or more than one isolated or purified single domain antibody or antigen-binding fragment thereof of claim 1 and a pharmaceutically-acceptable carrier, diluent, or excipient.