Human blood-brain barrier targeting antibodies

Patent metadata

Field	Value
Publication number	US-12492251-B2
Application number	US-202117759854-A
Country	US
Kind code	B2
Filing date	Jan 28, 2021
Priority date	Jan 28, 2020
Publication date	Dec 9, 2025
Grant date	Dec 9, 2025

Abstract

The present invention provides antibodies or antigen-binding fragments thereof including single chain variable fragment (scFv) antibodies that specifically bind to and translocate the blood-brain barrier and methods of use.

First claim

What is claimed:

1 . An isolated blood-brain barrier (BBB)-selective antibody or antigen-binding fragment thereof comprising:
(a) a heavy chain domain comprising a CDRH1 region comprising SEQ ID NO:26 (GFTFSGYW), a CDHR2 region comprising SEQ ID NO:27 (IKGDGTDI), and a CDHR3 region comprising SEQ ID NO:28 (ARDLRQTHWFDS), and a light chain domain comprising CDRL1 region comprising SEQ ID NO:29 (SLRSYY), a CDRL2 region comprising the amino acid sequence GE, and a CDRL3 comprising SEQ ID NO: 30 (SSRDTSGNHVL); (b) a heavy chain domain comprising a CDRH1 region comprising SEQ ID NO:2 (GFTFSSYA), a CDHR2 region comprising SEQ ID NO:3 (ISYDGSNK), and a CDHR3 region comprising SEQ ID NO:4 (ARDSKGQSVRNRFDP), and a light chain domain comprising a CDRL1 region comprising SEQ ID NO:5 (NLRSYY), a CDRL2 region comprising the amino acid sequence AN, and a CDRL3 comprising SEQ ID NO: 6 (NSRDSSGNLVV); (c) a heavy chain domain comprising a CDRH1 region comprising SEQ ID NO:8 (GFTFSSYA), a CDHR2 region comprising SEQ ID NO:9 (ISGSGGST), and a CDHR3 region comprising SEQ ID NO:10 (ARGWKYFDY), and a light chain domain comprising a CDRL1 region comprising SEQ ID NO:11 (EGIYHW), a CDRL2 region comprising the amino acid sequence KA, and a CDRL3 comprising SEQ ID NO:12 (QQYHTISRT); (d) a heavy chain domain comprising a CDRH1 region comprising SEQ ID NO:14 (GFTFSSST), a CDHR2 region comprising SEQ ID NO:15 (VSYDGNTQ), and a CDHR3 region comprising SEQ ID NO:16 (AGLWGSLLGYFQH), and a light chain domain comprising a CDRL1 region comprising SEQ ID NO:17 (QGVNNY), a CDRL2 region comprising the amino acid sequence AA, and a CDRL3 comprising SEQ ID NO:18 (QQAHSFPPT); (e) a heavy chain domain comprising a CDRH1 region comprising SEQ ID NO:20 (GFTFSTYW), a CDHR2 region comprising SEQ ID NO:21 (INQDGTAE), and a CDHR3 region comprising SEQ ID NO:22 (ATPTGDSDY), and a light chain domain comprising a CDRL1 region comprising SEQ ID NO:23 (SLRSYY), a CDRL2 region comprising the amino acid sequence GQ, and a CDRL3 comprising SEQ ID NO:24 (HSRDSSGNHVL); (f) a heavy chain domain comprising a CDRH1 region comprising SEQ ID NO:32 (GFTFSTYW), a CDHR2 region comprising SEQ ID NO:33 (INQDGTAE), and a CDHR3 region comprising SEQ ID NO:34 (ATPTGDSDY), and a light chain domain comprising a CDRL1 region comprising SEQ ID NO:35 (QDIGNY), a CDRL2 region comprising the amino acid sequence DA, and a CDRL3 comprising SEQ ID NO:36 (QKLSSYPLT); (g) a heavy chain domain comprising a CDRH1 region comprising SEQ ID NO:38 (GFTFSNYA), a CDHR2 region comprising SEQ ID NO:39 (ISGSGSST), and a CDHR3 region comprising SEQ ID NO:40 (AKTSGWPYYFDY), and a light chain domain comprising a CDRL1 region comprising SEQ ID NO:41 (SSNIGNNY), a CDRL2 region comprising the amino acid sequence DN, and a CDRL3 comprising SEQ ID NO:42 (CSYAGSSTLV); (h) a heavy chain domain comprising a CDRH1 region comprising SEQ ID NO:44 (GFTFSSYA), a CDHR2 region comprising SEQ ID NO:45 (VSGTGVST), and a CDHR3 region comprising SEQ ID NO:46 (ARGLDWKSTPIDY), and a light chain domain comprising a CDRL1 region comprising SEQ ID NO:47 (QSISGW), a CDRL2 region comprising the amino acid sequence GA, and a CDRL3 comprising SEQ ID NO:48 (LQDYNGWT); (i) a heavy chain domain comprising a CDRH1 region comprising SEQ ID NO:50 (GFTVSSNY), a CDHR2 region comprising SEQ ID NO:51 (IKQDGSEK), and a CDHR3 region comprising SEQ ID NO:52 (ARGGEEKNSGYYGDY), and a light chain domain comprising a CDRL1 region comprising SEQ ID NO:53 (SLRSYY), a CDRL2 region comprising the amino acid sequence QD, and a CDRL3 comprising SEQ ID NO:54 (QAWDSSTAHYV); (j) a heavy chain domain comprising a CDRH1 region comprising SEQ ID NO:56 (GFTFSSYV), a CDHR2 region comprising SEQ ID NO:57 (ISGSGGST), and a CDHR3 region comprising SEQ ID NO:58 (AKQNWYFDL), and a light chain domain comprising a CDRL1 region comprising SEQ ID NO:59 (SLRSYY), a CDRL2 region comprising the amino acid sequence GE, and a CDRL3 comprising SEQ ID NO:60 (NSRDSRGTHLEV); (k) a heavy chain domain comprising a CDRH1 region comprising SEQ ID NO:62 (GFTFSSYA), a CDHR2 region comprising SEQ ID NO:63 (ISGSGGST), and a CDHR3 region comprising SEQ ID NO:64 (AKSQGWAGDFDF), and a light chain domain comprising a CDRL1 region comprising SEQ ID NO:65 (SSDIGTYNY), a CDRL2 region comprising the amino acid sequence EV, and a CDRL3 comprising SEQ ID NO:66 (CSYAGSSTLV); or (l) a heavy chain domain comprising a CDRH1 region comprising SEQ ID NO:68 (GFTFSSYA), a CDHR2 region comprising SEQ ID NO:69 (ISSNGAIT), and a CDHR3 region comprising SEQ ID NO:70 (VKDLKPSSWPPIYFDY), and a light chain domain comprising a CDRL1 region comprising SEQ ID NO:71 (SLRTYY), a CDRL2 region comprising the amino acid sequence AN, and a CDRL3 comprising SEQ ID NO:72 (NSRDSSGNHHVV).

2 . The isolated BBB-selective antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody comprises an amino acid sequence selected from:
(a) SEQ ID NO:25 or a sequence having at least 90% identity to SEQ ID NO:25; (b) SEQ ID NO: 1 or a sequence having at least 90% identity to SEQ ID NO:1; (c) SEQ ID NO:7 or a sequence having at least 90% identity to SEQ ID NO:7; (d) SEQ ID NO:13 or a sequence having at least 90% identity to SEQ ID NO:13; (e) SEQ ID NO:19 or a sequence having at least 90% identity to SEQ ID NO:19; (f) SEQ ID NO:31 or a sequence having at least 90% identity to SEQ ID NO:31; (g) SEQ ID NO:37 or a sequence having at least 90% identity to SEQ ID NO:37; (h) SEQ ID NO:43 or a sequence having at least 90% identity to SEQ ID NO:43; (i) SEQ ID NO:49 or a sequence having at least 90% identity to SEQ ID NO:49; (j) SEQ ID NO:55 or a sequence having at least 90% identity to SEQ ID NO:55; (k) SEQ ID NO:61 or a sequence having at least 90% identity to SEQ ID NO:61; and (l) SEQ ID NO:67 or a sequence having at least 90% identity to SEQ ID NO:67.

3 . The isolated BBB-selective antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody comprises an amino acid sequence selected from: (a) SEQ ID NO:25; (b) SEQ ID NO:1; (c) SEQ ID NO:7; (d) SEQ ID NO:13; (e) SEQ ID NO:19; (f) SEQ ID NO:31; (g) SEQ ID NO:37; (h) SEQ ID NO:43; (1) SEQ ID NO:49; (j) SEQ ID NO: 55; (k) SEQ ID NO:61; and (l) SEQ ID NO:67.

4 . The BBB-selective antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof is a humanized antibody or humanized antigen-binding fragment thereof.

5 . The BBB-selective antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof is engrafted within a full IgG scaffold of human or other species origin or a scFv scaffold of human or other species of origin.

6 . The BBB-selective antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody is a single chain variable fragment (scFv).

7 . The BBB-selective antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof can bind the BBB and translocate across the BBB.

8 . The BBB-selective antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment thereof specifically binds to the brain.

9 . The BBB-selective antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody is directly or indirectly linked to an agent.

10 . The BBB-selective antibody or antigen-binding fragment thereof of claim 9 , wherein the agent is selected from the group consisting of a therapeutic agent, a pharmaceutical agent, a diagnostic agent, an imaging agent, a detection agent, an immunological therapeutic construct, and a combination thereof.

11 . The BBB-selective antibody or a

Assignees

• Wisconsin Alumni Res Found

Inventors

• Shusta Eric V
• Stutz Charles C
• Goulatis Loukas
• Georgieva Julia

Classifications

• C12N15/63

  Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression · CPC title

• C07K2317/622

  Single chain antibody (scFv) · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title

• A61K2039/505

  comprising antibodies · CPC title