NZ763370B2 - Bispecific antibodies and methods of making and using thereof - Google Patents

Bispecific antibodies and methods of making and using thereof Download PDF

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Publication number
NZ763370B2
NZ763370B2 NZ763370A NZ76337018A NZ763370B2 NZ 763370 B2 NZ763370 B2 NZ 763370B2 NZ 763370 A NZ763370 A NZ 763370A NZ 76337018 A NZ76337018 A NZ 76337018A NZ 763370 B2 NZ763370 B2 NZ 763370B2
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NZ
New Zealand
Prior art keywords
green
angela
annotation
seq
cancer
Prior art date
Application number
NZ763370A
Other versions
NZ763370A (en
Inventor
Bill Brady
Katrina Bykova
Jonathan K Fallon
Zeren Gao
Brian Kovacevich
Blair Renshaw
phil Tan
Dong Xia
Yi Zhu
Original Assignee
Systimmune Inc
Filing date
Publication date
Application filed by Systimmune Inc filed Critical Systimmune Inc
Priority claimed from PCT/US2018/058810 external-priority patent/WO2019090002A1/en
Publication of NZ763370A publication Critical patent/NZ763370A/en
Publication of NZ763370B2 publication Critical patent/NZ763370B2/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/64—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising a combination of variable region and constant region components
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

The disclosure provides bispecific antibodies having the binding specificity to at least two of human CTLA4, PD-1 or PD-L1. In one embodiment, the bispecific antibody comprises IgG domains having heavy chains and light chains, and two scFv components being connected to either C-terminal of the heavy chains or N-terminal of the light chains, wherein the IgG domains have the binding specificity to a first antigen, wherein the scFv components have the binding specificity to a second antigen, and wherein the first antigen and the second antigen are different and are independently selected from a-CTLA4, a-PD-1, and a-PD-L1.

Claims (29)

1. A bispecific antibody, comprising IgG domains having heavy chains and light , and two scFv components being connected to either C terminal of the heavy chains or N terminal of the light chains, wherein the IgG domains have a first binding specificity to a-CTLA4, wherein the scFv components have a second binding specificity to a-PD-1 or a-PD-L1, and wherein: i. the IgG domains comprise light chain complementarity determining s 1-3 (LCDR1- 3) as set forth in LCDR1-3 of SEQ ID No. 94 and heavy chain complementarity determining regions 1-3 (HCDR1-3) as set forth in HCRD1-3 of SEQ ID No. 92; and the scFv components comprise LCDR1-3 as set forth in LCDR1-3 of SEQ ID No. 98 and HCDR1-3 as set forth in HCDR1-3 of SEQ ID No. 96; ii. the IgG domains comprise LCDR1-3 as set forth in LCDR1-3 of SEQ ID No. 94 and HCDR1-3 as set forth in HCDR1-3 of SEQ ID No. 92; and the scFv ents comprise LCDR1-3 as set forth in LCDR1-3 of SEQ ID No. 122 and HCDR1-3 as set forth in HCDR1-3 of SEQ ID No: 120.
2. The bispecific antibody of claim 1, wherein: i. the scFv ents comprise a light chain variable region comprising an amino acid sequence having at least 98% sequence identity to SEQ ID No. 98 and a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity to SEQ ID No. 96; and the IgG s comprise a light chain le region comprising an amino acid sequence having at least 98% identity to SEQ ID No. 94 and a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity to SEQ ID No. 92; ii. the scFv components comprise a light chain variable region comprising an amino acid sequence having at least 98% sequence identity to SEQ ID No. 122, and a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity to SEQ ID No. 120; and the IgG variable domains se a light chain variable region comprising an amino acid sequence having at least 98% identity to SEQ ID No. 94 and a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity to SEQ ID No.
3. The bispecific dy of claim 1, comprising: [Annotation] Angela.Green None set by Angela.Green [Annotation] Angela.Green MigrationNone set by Angela.Green ation] Angela.Green Unmarked set by Angela.Green [Annotation] Angela.Green None set by Angela.Green [Annotation] Angela.Green ionNone set by Angela.Green [Annotation] Angela.Green Unmarked set by Angela.Green i. an amino acid sequence having at least 98% sequence identity to SEQ ID No. 2 and an amino acid ce having at least 98% sequence identity to SEQ ID No. 4; or ii. an amino acid sequence having at least 98% sequence identity to SEQ ID No. 8 and an amino acid sequence having at least 98% sequence identity to SEQ ID No. 4.
4. The bispecific antibody of any one of claims 1 to 3, wherein the two scFv components are connected to the C terminal of the heavy chain.
5. The bispecific antibody of any one of claims 1 to 3, wherein the two scFv components are ted to the N terminal of the light chain.
6. The bispecific antibody of any one of claims 1 to 5, wherein the bispecific antibody is an isolated monoclonal antibody.
7. The bispecific antibody of any one of claims 1 to 6, wherein neither the first binding specificity to a-CTLA4 nor the second g icity to a-PD-1 or 1 has a Kd greater than 70nM.
8. The bispecific antibody of any one of claims 1 to 7, comprising a human framework region.
9. The bispecific antibody of any one of claims 1 to 8, wherein the antibody is a humanized antibody, a chimeric antibody, or a recombinant antibody.
10. The bispecific antibody of any one of claims 1 to 9, wherein the IgG domain comprises an IgG1 constant region, wherein the IgG1 constant region comprises an amino acid sequence having at least 98% similarity with SEQ ID No. 136.
11. An isolated nucleic acid encoding the bispecific antibody of any one of claims 1 to 10.
12. An expression vector comprising the isolated nucleic acid of claim 11.
13. T he expression vector of claim 12, wherein the vector is expressible in a cell.
14. An isolated host cell comprising the nucleic acid of claim 11.
15. A n ed host cell comprising the expression vector of claim 12 or 13.
16. The isolated host cell of claim 14 or 15, wherein the host cell is a prokaryotic cell or a eukaryotic cell.
17. A method of producing a ific antibody, sing culturing the host cell of any one of claims 14 to 16 so that the bispecific antibody is produced.
18. An immunoconjugate comprising the bispecific antibody of any one of claim 1 to 10 and a cytotoxic agent.
19. The immunoconjugate according to claim 18, wherein the cytotoxic agent comprises a herapeutic agent, a growth inhibitory agent, a toxin, or a radioactive isotope.
20. A pharmaceutical ition, comprising the bispecific antibody of any one of claims 1 to 10 and a pharmaceutically acceptable carrier. [Annotation] Angela.Green None set by Angela.Green [Annotation] Angela.Green MigrationNone set by Angela.Green [Annotation] Angela.Green Unmarked set by Angela.Green [Annotation] Angela.Green None set by Angela.Green [Annotation] Angela.Green MigrationNone set by .Green [Annotation] Angela.Green Unmarked set by Angela.Green
21. The pharmaceutical composition of claim 20, further comprising radioisotope, radionuclide, a toxin, a therapeutic agent, a chemotherapeutic agent or a combination thereof.
22. A pharmaceutical ition, comprising the immunoconjugate of claim 18 or 19 and a pharmaceutically acceptable carrier.
23. Use of the bispecific antibody of any one of claims 1 to 10 in the manufacture of a ment for treating a subject with a cancer that is responsive to regulation of CTLA4, and PD-1 or PD-L1 checkpoint ns.
24. The use of claim 23, n the cancer comprises cells expressing PD-L1.
25. The use of claim 23 or 24, wherein the cancer comprises breast cancer, colorectal cancer, pancreatic cancer, head and neck cancer, ma, ovarian cancer, te cancer, non-small lung cell cancer, small cell lung cancer, glioma, geal cancer, nasopharyngeal cancer, kidney , gastric cancer, liver cancer, r cancer, cervical cancer, brain cancer, lymphoma, leukaemia, or myeloma.
26. The use of any one of claims 23 to 25, wherein the medicament is to be co-administered with an effective amount of a therapeutic agent.
27. The use of claim 26, wherein the eutic agent comprises an antibody, a chemotherapy agent, an enzyme, or a combination thereof.
28. The use of claim 27, wherein the therapeutic agent comprises capecitabine, cisplatin, trastuzumab, fulvestrant, tamoxifen, letrozole, exemestane, anastrozole, aminoglutethimide, testolactone, vorozole, tane, fadrozole, letrozole, erlotinib, lafatinib, dasatinib, gefitinib, imatinib, pazopinib, lapatinib, nib, nilotinib, sorafenib, nab-palitaxel, a derivative or a combination thereof.
29. The use of any one of claims 23 to 28, wherein the subject is a human. [Annotation] Angela.Green None set by Angela.Green [Annotation] Angela.Green MigrationNone set by Angela.Green [Annotation] Angela.Green Unmarked set by Angela.Green [Annotation] Angela.Green None set by .Green [Annotation] Angela.Green ionNone set by Angela.Green [Annotation] Angela.Green Unmarked set by Angela.Green [Annotation] Angela.Green None set by .Green ation] Angela.Green MigrationNone set by Angela.Green [Annotation] Angela.Green Unmarked set by Angela.Green [Annotation] Angela.Green None set by Angela.Green [Annotation] Angela.Green MigrationNone set by Angela.Green [Annotation] Angela.Green Unmarked set by Angela.Green CT4x PL224D1 lgG1 null -A- Fc-PD224D1 scFV lgG1 null -EI- lgG1 null lsotype Control 0.1 1 10 100 Antibody Concentration (nM) [Annotation] Angela.Green None set by Angela.Green ation] Angela.Green MigrationNone set by Angela.Green ation] Angela.Green Unmarked set by Angela.Green [Annotation] Angela.Green None set by Angela.Green [Annotation] Angela.Green MigrationNone set by Angela.Green [Annotation] Angela.Green Unmarked set by Angela.Green -e- CT4 X PL221GS lgG1 null -E- CT4 X PL221G5 lgG1 -A- CT4X PD224D1 lgG1 null -V- CT4X PD224D1 lgG1 null CT4 X PD224D1 lgG1 0.0001 0.001 0.01 0.1 1 10 100 Treatment (nM) [Annotation] Angela.Green None set by Angela.Green ation] Angela.Green ionNone set by Angela.Green [Annotation] Angela.Green Unmarked set by Angela.Green [Annotation] Angela.Green None set by Angela.Green [Annotation] Angela.Green ionNone set by Angela.Green [Annotation] Angela.Green Unmarked set by Angela.Green
NZ763370A 2018-11-01 Bispecific antibodies and methods of making and using thereof NZ763370B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201762580845P 2017-11-02 2017-11-02
PCT/US2018/058810 WO2019090002A1 (en) 2017-11-02 2018-11-01 Bispecific antibodies and methods of making and using thereof

Publications (2)

Publication Number Publication Date
NZ763370A NZ763370A (en) 2024-10-25
NZ763370B2 true NZ763370B2 (en) 2025-01-28

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