US2017198051A1PendingUtilityA1

Multivalent and multispecific ox40-binding fusion proteins

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Assignee: INHIBRX LPPriority: Jan 11, 2016Filed: Jan 11, 2017Published: Jul 13, 2017
Est. expiryJan 11, 2036(~9.5 yrs left)· nominal 20-yr term from priority
Inventors:Brendan P. EckelmanJohn C. TimmerChelsie HataKyle S. JonesAbrahim HussainAmir S. RazaiBryan BecklundRajay PanditMike KaplanLucas RasonQuinn Deveraux
A61P 35/00A61P 37/04A61P 37/02A61P 29/00C07K 2317/52C07K 2317/33C07K 2317/76C07K 2319/00C07K 2317/569C07K 16/2827C07K 2317/35C07K 2317/75C07K 2317/31C07K 2317/24C07K 16/2878A61K 2039/505
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Claims

Abstract

This invention relates generally to molecules that specifically engage OX40, a member of the TNF receptor superfamily (TNFRSF). More specifically this invention relates to multivalent and multispecific molecules that bind at least OX40.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . An isolated polypeptide that binds OX40 and comprises a plurality of Tumor Necrosis Factor receptor superfamily (TNFRSF) binding domain (TBDs), wherein at least a first TBD (TBD1) binds OX40. 
     
     
         2 . An isolated polypeptide that binds PDL1 and comprises a plurality of polypeptide binding domains (BDs), wherein at least a first BD (BD1) binds PDL1. 
     
     
         3 . An isolated polypeptide that binds PDL1 and OX40 and comprises a plurality of polypeptide binding domains (BDs) and a plurality of Tumor Necrosis Factor receptor superfamily (TNFRSF) binding domain (TBDs), wherein at least a first binding domain (BD1) binds PLD1 and at least a first TNFRSF binding domain (TBD1) binds OX40. 
     
     
         4 . The isolated polypeptide of  claim 1 , wherein the isolated polypeptide is monospecific. 
     
     
         5 . The isolated polypeptide of  claim 1 , wherein the isolated polypeptide is multispecific. 
     
     
         6 . The isolated polypeptide of  claim 1 , wherein the isolated polypeptide is bispecific. 
     
     
         7 . The isolated polypeptide of  claim 1 , the polypeptide comprises at least a second TBD (TBD2) that binds a second TNFRSF member. 
     
     
         8 . The isolated polypeptide of  claim 1 , wherein each of TBD in the plurality of TBDs binds OX40. 
     
     
         9 . The isolated polypeptide of  claim 8 , wherein the plurality of TBDs binds the same epitope on OX40. 
     
     
         10 . The isolated polypeptide of  claim 8 , wherein at least two TBDs in the plurality of TBDs bind a different epitope on OX40. 
     
     
         11 . The isolated polypeptide of  claim 8 , wherein the plurality of TBDs comprises at least four TBDs. 
     
     
         12 . The isolated polypeptide of  claim 8 , wherein the plurality of TBDs comprises at least six TBDs. 
     
     
         13 . The isolated polypeptide of  claim 2 , wherein the polypeptide comprises at least a second BD (BD2) that binds a second antigen. 
     
     
         14 . The isolated polypeptide of  claim 2 , wherein each BD in the plurality of BDs binds PDL1. 
     
     
         15 . The isolated polypeptide of  claim 14 , wherein the plurality of BDs binds the same epitope on PDL1. 
     
     
         16 . The isolated polypeptide of  claim 14 , wherein at least two BDs in the plurality of BDs bind a different epitope on PDL1. 
     
     
         17 . The isolated polypeptide of  claim 13 , wherein the plurality of BDs comprises at least four BDs. 
     
     
         18 . The isolated polypeptide of  claim 13 , wherein the plurality of BDs comprises at least six BDs. 
     
     
         19 . The isolated polypeptide of  claim 1 , wherein each of the TBD in the plurality of TBDs or each of the BDs in the plurality of BDs are operably linked via a linker polypeptide. 
     
     
         20 . The isolated polypeptide of  claim 1 , wherein the isolated polypeptide comprises at least one binding domain that binds a target, provided that the target is not a TNFRSF member. 
     
     
         21 . The isolated polypeptide of  claim 1 , wherein at least one of the TBD in the plurality of TBDs binds a second TNFRSF member selected from the group consisting of DR5, GITR, and CD137. 
     
     
         22 . The isolated polypeptide of  claim 1 , wherein the isolated polypeptide comprises a heterodimerization domain. 
     
     
         23 . The isolated polypeptide of  claim 1 , wherein the isolated polypeptide comprises an immunoglobulin Fc region polypeptide. 
     
     
         24 . The isolated polypeptide of  claim 23 , wherein the immunoglobulin Fc region polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-6. 
     
     
         25 . The isolated polypeptide of  claim 1 , wherein at least one TBD in the plurality of TBDs or at least one BD in the plurality of BDs comprises an antibody or antigen-binding fragment thereof. 
     
     
         26 . The isolated polypeptide of  claim 1 , wherein each TBD in the plurality of TBDs or at least one BD in the plurality of BDs comprises an antibody or antigen-binding fragment thereof. 
     
     
         27 . The isolated polypeptide of  claim 25 , wherein the antibody or antigen-binding fragment thereof is a scFv, a Fab, a single domain antibody (sdAb), a V NAR , or a VHH. 
     
     
         28 . The isolated polypeptide of  claim 25 , wherein the antibody or antigen-binding fragment is a sdAb. 
     
     
         29 . The isolated polypeptide of  claim 28 , wherein the sdAb is a human or humanized sdAb. 
     
     
         30 . The isolated polypeptide of  claim 28 , wherein the sdAb is VHH, V NAR , an engineered VH domain or an engineered VK domain. 
     
     
         31 . The isolated polypeptide of  claim 30 , wherein the sdAb is generated from a cartilaginous fish heavy chain only antibody. 
     
     
         32 . The isolated polypeptide of  claim 1 , wherein at least one the TNFRSF binding domains comprises a non-antibody scaffold protein. 
     
     
         33 . The isolated polypeptide of  claim 32 , wherein the non-antibody scaffold protein is an ankyrin repeat protein, a darpin, an avimer, an anticalin/lipocalin, a centyrin, or a fynomer. 
     
     
         34 . The isolated polypeptide of  claim 1 , wherein the polypeptide comprises an amino acid sequence that binds OX40 selected from the group consisting of SEQ ID NO: 16-29 and 377-386. 
     
     
         35 . The isolated polypeptide of  claim 1 , wherein the polypeptide comprises an amino acid sequence that binds OX40 and comprises a complementarity determining region 1 (CDR1) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 30, 36, and 44; a complementarity determining region 2 (CDR2) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 31, 35, and 37; and a complementarity determining region 3 (CDR3) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 32-34, 48-43, and 45. 
     
     
         36 . The isolated polypeptide of  claim 2 , wherein the polypeptide comprises an amino acid sequence that binds PDL1 selected from the group consisting of SEQ ID NO: 52-57. 
     
     
         37 . The isolated polypeptide of  claim 2 , wherein the polypeptide comprises an amino acid sequence that binds PDL1 and comprises a complementarity determining region 1 (CDR1) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 58, 61, and 64; a complementarity determining region 2 (CDR2) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 59, 62, 65, and 69; and a complementarity determining region 3 (CDR3) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 60, 63, 66-68, and 70. 
     
     
         38 . The isolated polypeptide of  claim 3 , wherein the polypeptide comprises a first amino acid sequence that binds OX40 selected from the group consisting of SEQ ID NO: 52-57, and a second amino acid sequence that binds PDL1 selected from the group consisting of SEQ ID NO: 52-57. 
     
     
         39 . The isolated polypeptide of  claim 3 , wherein the polypeptide comprises an amino acid sequence that binds OX40 and comprises a complementarity determining region 1 (CDR1) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 30, 36, and 44; a complementarity determining region 2 (CDR2) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 31, 35, and 37; and a complementarity determining region 3 (CDR3) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 32-34, 48-43, and 45, and wherein the polypeptide comprises an amino acid sequence that binds PDL1 and comprises a CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 58, 61, and 64; a CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 59, 62, 65, and 69; and a CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 60, 63, 66-68, and 70. 
     
     
         40 . The isolated polypeptide of  claim 1 , wherein the polypeptide is tetravalent. 
     
     
         41 . The isolated polypeptide of  claim 40 , wherein the polypeptide comprises the structure: VHH-Linker-VHH-Linker-Hinge-Fc, where the VHH is a humanized or fully human VHH sequence. 
     
     
         42 . The isolated polypeptide of  claim 1 , wherein the polypeptide is hexavalent. 
     
     
         43 . The isolated polypeptide of  claim 42 , wherein the polypeptide comprises the structure: VHH-Linker-VHH-Linker-VHH-Linker-Hinge-Fc, where the VHH is a humanized or fully human VHH sequence. 
     
     
         44 . An isolated polypeptide that binds OX40 and PDL1, wherein the polypeptide comprises an amino acid sequence that is selected from the group consisting of SEQ ID NO: 387-394. 
     
     
         45 . Use of the polypeptide of  claim 1  for treating neoplasms. 
     
     
         46 . Use of the polypeptide of  claim 1  for modulating immune cells to enhance tumor destruction. 
     
     
         47 . Use of the polypeptide of  claim 1  for treating an inflammatory disorder.

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