US2020299407A1PendingUtilityA1

Trispecific antibodies specific for her2 and a blood brain barrier receptor and methods of use

67
Assignee: HOFFMANN LA ROCHEPriority: Jun 24, 2015Filed: Dec 20, 2019Published: Sep 24, 2020
Est. expiryJun 24, 2035(~8.9 yrs left)· nominal 20-yr term from priority
Inventors:Christian KleinJulia E. KruegerEkkehard MoessnerJens Niewoehner
C07K 16/2881A61K 2039/507C07K 2317/622C07K 2317/41A61K 2039/505C07K 2317/34C07K 2317/515A61P 35/00C07K 16/32C07K 2317/73C07K 2317/92C07K 2317/732C07K 2317/94C07K 2317/24C07K 2317/734C07K 2317/33C07K 2317/51C07K 2317/31C07K 16/18C07K 2317/60
67
PatentIndex Score
0
Cited by
0
References
0
Claims

Abstract

The present invention relates to trispecific antibodies binding to HER2 and a blood-brain barrier receptor (BBB-R), methods for their production, pharmaceutical compositions containing said antibodies, and uses thereof.

Claims

exact text as granted — not AI-modified
1 . A trispecific antibody specifically binding to HER2 and a blood-brain barrier receptor (BBB-R), comprising a first monovalent antigen binding site specific for extracellular domain II of HER2 and a second monovalent antigen binding site specific for extracellular domain IV of HER2, and a third monovalent antigen binding site specific for a BBB-R. 
     
     
         2 . The trispecific antibody of  claim 1 , wherein the BBB-R of the third antigen binding site is selected from the group consisting of transferrin receptor (TfR), insulin receptor, insulin-like growth factor receptor (IGF receptor), low density lipoprotein receptor-related protein 8 (LRP8), low density lipoprotein receptor-related protein 1 (LRP1), and heparin-binding epidermal growth factor-like growth factor (HB-EGF). 
     
     
         3 . The trispecific antibody of  claim 1  wherein the third antigen binding site is specific for the transferrin receptor 
     
     
         4 . The trispecific antibody of  claim 1  wherein the third antigen binding site specifically binds to an epitope in the transferrin receptor comprised within the amino acid sequence of SEQ ID NO: 202, 203 and/or 204. 
     
     
         5 . The trispecific antibody  claim 1 , comprising a first Fab molecule capable of specific binding to extracellular domain II of HER2 and a second Fab molecule capable of specific binding to extracellular domain IV of HER2, wherein the sequence of the variable light chain of the first Fab molecule is identical to the sequence of the variable light chain of the second Fab molecule. 
     
     
         6 . The trispecific antibody of  claim 5 , comprising
 (a) a first heavy chain comprising   a heavy chain CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 55, SEQ ID NO: 58 and SEQ ID NO: 14;   a heavy chain CDR 2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 77; SEQ ID NO: 15 and SEQ ID NO: 60 and   a heavy chain CDR 3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 56 or SEQ ID NO: 59 and SEQ ID NO: 16, and   (b) a second heavy chain comprising a heavy chain CDR1 comprising an amino acid sequence of SEQ ID NO: 20, a heavy chain CDR2 comprising an amino acid sequence of SEQ ID NO: 29 and a heavy chain CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 30 and SEQ ID NO: 79   (c) a first and a second light chain, wherein the variable light chains of the first and second light chain comprise the CDRs comprising an amino acid sequence of SEQ ID NO: 89, SEQ ID NO: 90 and SEQ ID NO: 19.   
     
     
         7 . The trispecific antibody of  claim 5 , comprising two variable light chains comprising an amino acid sequence of SEQ ID NO: 54, a first heavy chain comprising a variable heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 64, SEQ ID NO: 70 and SEQ ID NO: 68, and a second heavy chain comprising a variable heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 92 and SEQ ID NO: 117. 
     
     
         8 . The trispecific antibody of  claim 1 , comprising a first Fab molecule capable of specific binding to extracellular domain II of HER2 and a second Fab molecule capable of specific binding to extracellular domain IV of HER2, wherein either the variable regions or the constant regions of the heavy and light chain of at least one Fab fragment are exchanged. 
     
     
         9 . The trispecific antibody of  claim 8 , wherein the first Fab molecule comprises
 a heavy chain CDR1 comprising an amino acid sequence of SEQ ID NO: 14, a heavy chain CDR2 comprising an amino acid sequence of SEQ ID NO: 15 and a heavy chain CDR3 comprising an amino acid sequence of SEQ ID NO: 16; and a light chain CDR1 comprising an amino acid sequence of SEQ ID NO: 11;   a light chain CDR2 comprising an amino acid sequence of SEQ ID NO: 12 and a light chain CDR3 comprising an amino acid sequence of SEQ ID NO: 13, and wherein the second Fab molecule comprises   a heavy chain CDR1 comprising an amino acid sequence of SEQ ID NO: 20; a heavy chain CDR2 comprising an amino acid sequence of SEQ ID NO: 108; a heavy chain CDR3 comprising an amino acid sequence of SEQ ID NO: 79; and a light chain CDR1 comprising an amino acid sequence of SEQ ID NO: 107, a light chain CDR2 comprising an amino acid sequence of SEQ ID NO: 18 and a light chain CDR3 comprising an amino acid sequence of SEQ ID NO: 19.   
     
     
         10 . The trispecific antibody of  claim 8 , wherein the first Fab molecule comprises
 a heavy chain CDR1 comprising an amino acid sequence of SEQ ID NO: 14, a heavy chain CDR2 comprising an amino acid sequence of SEQ ID NO: 15 and a heavy chain CDR3 comprising an amino acid sequence of SEQ ID NO: 16; and a light chain CDR1 comprising an amino acid sequence of SEQ ID NO: 11, a light chain CDR2 comprising an amino acid sequence of SEQ ID NO: 12 and a light chain CDR3 comprising an amino acid sequence of SEQ ID NO: 13, and wherein the second Fab molecule comprises   a heavy chain CDR1 comprising an amino acid sequence of SEQ ID NO: 20, a heavy chain CDR2 comprising an amino acid sequence of SEQ ID NO: 29, and a heavy chain CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 79, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 87, SEQ ID NO: 88; and a light chain CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 104, SEQ ID NO: 103 and SEQ ID NO: 158; a light chain CDR2 comprising an amino acid sequence of SEQ ID NO: 18 and a light chain CDR3 comprising an amino acid sequence of SEQ ID NO: 19.   
     
     
         11 . The trispecific antibody of  claim 8 , wherein the first Fab molecule comprises
 a variable heavy chain comprising an amino acid sequence of SEQ ID NO: 22 and a variable light chain comprising an amino acid sequence of SEQ ID NO: 24 and wherein the second Fab molecule comprises an amino acid sequence of SEQ ID NO: 105 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 106.   
     
     
         12 . The trispecific antibody of  claim 1 , wherein the third antigen binding site specific for a BBB-R is a scFv or a scFab. 
     
     
         13 . The trispecific antibody of  claim 12 , wherein the scFv or scFab is connected to the N-terminus of an IgG molecule comprsing the first and second antigen binding site. 
     
     
         14 . The trispecific antibody of  claim 12 , wherein the scFv or scFab is connected to the C-terminus of the first or second subunit of the Fc domain. 
     
     
         15 . The trispecific antibody of  claim 1 , wherein the third antigen binding site comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 186, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 187 and a heavy chain CDR3 comprising the amino acid sequence selected from the group of SEQ ID NO: 188, SEQ ID NO: 206 or SEQ ID NO: 174; and a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 189, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 190 and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:191. 
     
     
         16 . The trispecific antibody of  claim 1 , wherein the third antigen binding site comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 172, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 173 and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 174; and a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 175, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 176 and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:177. 
     
     
         17 . The trispecific antibody of  claim 1 , wherein the third antigen binding site comprises a variable heavy chain comprising an amino acid sequence of SEQ ID NO: 178 and a variable light chain comprising an amino acid sequence of SEQ ID NO: 179 or a humanized version thereof. 
     
     
         18 . The trispecific antibody of  claim 1 , wherein the third antigen binding site comprises a variable heavy chain comprising an amino acid sequence of SEQ ID NO: 192 or SEQ ID NO: 205 and a variable light chain comprising an amino acid sequence of SEQ ID NO: 193. 
     
     
         19 . The trispecific antibody of  claim 1 , wherein the third antigen binding site comprises a heavy chain CDR1 of SEQ ID NO: 180, a heavy chain CDR2 of SEQ ID NO: 181 and a heavy chain CDR3 of SEQ ID NO: 182; and a light chain CDR1 of SEQ ID NO: 183, a light chain CDR2 of SEQ ID NO: 184 and a light chain CDR3 of SEQ ID NO: 185 
     
     
         20 . The trispecific antibody of  claim 1 , wherein the third antigen binding site comprises a variable heavy chain comprising an amino acid sequence of SEQ ID NO: 166 and a variable light chain comprising an amino acid sequence of SEQ ID NO: 167 or a humanized version thereof. 
     
     
         21 . The trispecific antibody of  claim 1 , wherein the third antigen binding site comprises a variable heavy chain comprising an amino acid sequence of SEQ ID NO: 92, SEQ ID NO: 195, SEQ ID NO: 196, SEQ ID NO: 197, SEQ ID NO: 198, SEQ ID NO: 199, or SEQ ID NO: 200, and a variable light chain comprising an amino acid sequence selected from the group of SEQ ID NO: 201, SEQ ID NO: 207, SEQ ID NO: 208, or SEQ ID NO:209. 
     
     
         22 . A pharmaceutical composition comprising a bispecific antibody of  claim 1 . 
     
     
         23 . The trispecific antibody of  claim 1  for the treatment of cancer. 
     
     
         24 . The trispecific antibody of  claim 1  for use in the treatment of cancer. 
     
     
         25 . The trispecific antibody of  claim 1  for use as a medicament. 
     
     
         26 . Use of the trispecific antibody of  claim 1  in the manufacture of a medicament. 
     
     
         27 . The use of  claim 25 , wherein the medicament is for treatment of cancer. 
     
     
         28 . The treatment of  claim 23 , wherein the cancer is a HER2-positive cancer with brain metastases. 
     
     
         29 . A nucleic acid sequence comprising a sequence encoding a heavy chain of a trispecific antibody of  claim 1 . 
     
     
         30 . A nucleic acid sequence comprising a sequence encoding a light chain of a trispecific antibody of  claim 1 . 
     
     
         31 . An expression vector comprising a nucleic acid sequence of  claim 29 . 
     
     
         32 . A prokaryotic or eukaryotic host cell comprising a vector according to  claim 31 . 
     
     
         33 . A method of producing an antibody comprising culturing the host cell of  claim 32  so that the antibody is produced. 
     
     
         34 . The invention as described herein, especially with reference to the foregoing examples.

Join the waitlist — get patent alerts

Track US2020299407A1 — get alerts on status changes and closely related new filings.

We store only your email — no account needed. See our privacy policy.