WO2019220204A2 - Antibodies against lif and dosage forms thereof - Google Patents

Antibodies against lif and dosage forms thereof Download PDF

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Publication number
WO2019220204A2
WO2019220204A2 PCT/IB2019/000541 IB2019000541W WO2019220204A2 WO 2019220204 A2 WO2019220204 A2 WO 2019220204A2 IB 2019000541 W IB2019000541 W IB 2019000541W WO 2019220204 A2 WO2019220204 A2 WO 2019220204A2
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WIPO (PCT)
Prior art keywords
amino acid
acid sequence
seq
set forth
cancer
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Ceased
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PCT/IB2019/000541
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English (en)
French (fr)
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WO2019220204A3 (en
Inventor
Joan Seoane Suarez
Judit Anido Folgueira
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Institucio Catalana de Recerca i Estudis Avancats ICREA
Fundacio Privada Institut dInvestigacio Oncologica Vall dHebron
Mosaic Biomedicals SL
Original Assignee
Institucio Catalana de Recerca i Estudis Avancats ICREA
Fundacio Privada Institut dInvestigacio Oncologica Vall dHebron
Mosaic Biomedicals SL
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Priority to CA3099406A priority Critical patent/CA3099406A1/en
Priority to EA202092632A priority patent/EA202092632A1/ru
Priority to CN201980046565.4A priority patent/CN112638941A/zh
Priority to SG11202011170YA priority patent/SG11202011170YA/en
Priority to EP19765782.8A priority patent/EP3794031A2/en
Priority to JP2020563980A priority patent/JP7536654B2/ja
Priority to AU2019269131A priority patent/AU2019269131B2/en
Priority to KR1020207035617A priority patent/KR20210008514A/ko
Application filed by Institucio Catalana de Recerca i Estudis Avancats ICREA, Fundacio Privada Institut dInvestigacio Oncologica Vall dHebron, Mosaic Biomedicals SL filed Critical Institucio Catalana de Recerca i Estudis Avancats ICREA
Priority to US17/055,279 priority patent/US20220064279A1/en
Publication of WO2019220204A2 publication Critical patent/WO2019220204A2/en
Publication of WO2019220204A3 publication Critical patent/WO2019220204A3/en
Anticipated expiration legal-status Critical
Priority to JP2024130558A priority patent/JP2024160301A/ja
Ceased legal-status Critical Current

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    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39591—Stabilisation, fragmentation
    • 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
    • C07K16/24—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • 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
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • 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
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
    • C07K2317/41—Glycosylation, sialylation, or fucosylation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
    • 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
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • 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
    • 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
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

  • anti-LIF antibodies that antagonize or block LIF activity.
  • the anti-LIF antibodies described herein are useful for the treatment of cancer.
  • certain anti-LIF antibodies when administered at a therapeutically effective dose resulted in superior and surprising efficacy in the reduction of tumor volumes in both mouse and non-human primate cancer models.
  • the current disclosure includes methods and pharmaceutical compositions of treating cancer using specific anti-LIF antibodies at specific dosages (both weight-based dosing and flat-dosing).
  • the recombinant antibody is administered at a dose of about 1125 milligrams. In certain embodiments, the recombinant antibody is administered at a dose of about 1500 milligrams. In certain embodiments, the recombinant antibody is administered at a dose of about 2000 milligrams.
  • the cancer comprises non-small cell lung cancer, epithelial ovarian carcinoma, or pancreatic adenocarcinoma.
  • the recombinant antibody is administered as a component of a pharmaceutical formulation, the pharmaceutical formulation comprising the recombinant antibody and further comprising a pharmaceutically acceptable excipient, carrier, or diluent.
  • the pharmaceutical formulation has a pH of about 6.0.
  • the pharmaceutical formulation comprises about 25mM histidine, about 6% sucrose, and about 0.01% polysorbate 80, wherein the recombinant antibody is included at a concentration of about 20 mg/mL.
  • the recombinant antibody is administered intravenously.
  • the recombinant antibody comprises one or more of a light chain framework 1 (VL-FR1) region amino acid sequence at least about 80%, 90%, 95%, 97%, 98%, or 99% identical to the amino acid sequence set forth in any one of SEQ ID NOs: 26-29, a light chain framework 2 (VL-FR2) region amino acid sequence at least about 80%, 90%, 95%, 97%, 98%, or 99% identical to the amino acid sequence set forth in any one of SEQ ID NOs: 30-33, a light chain framework 3 (VL-FR3) region amino acid sequence at least about 80%, 90%, 95%, 97%, 98%, or 99% identical to the amino acid sequence set forth in any one of SEQ ID NOs: 34- 37, and a light chain framework 4 (VL-FR4) region amino acid sequence at least about 80%, 90%, 95%, 97%, 98%, or 99% identical to the amino acid sequence set forth in any one of SEQ ID NOs: 38-40.
  • VL-FR1 light chain framework 1
  • Fig. 2A and 2B depicts a western blot showing inhibition of LIF-induced STAT3 phosphorylation humanized and parental 5D8 antibody.
  • Fig. 9A shows the effect of r5D8 on inhibition of growth of colorectal cancer cells in a syngeneic mouse model.
  • Fig. 12 shows data from mice bearing CT26 tumors treated twice weekly with PBS (control) or r5D8 administered intraperitoneally in the presence or absence of anti-CD4 and anti- CD8 depleting antibodies.
  • the graph shows individual tumor measurements at dl3 expressed as mean tumor volume + SEM. Statistical differences between groups was determined by unpaired non-parametric Mann-Whitney U-test. R5D8 inhibited the growth of CT26 tumors (*p ⁇ 0.05). The tumor growth inhibition by r5D8 was significantly reduced in the presence of anti-CD4 and anti-CD8 depleting antibodies (****p ⁇ 0.000l).
  • FIG. 16B and 16C illustrate ELISA analysis of LIF/mAb complexes binding to immobilized LIFR or gpl30.
  • Signals of species-specific peroxidase conjugated anti-IgG antibodies anti-human for (-) and h5D8, anti-rat for r5d8 and B09) detecting the antibody portion of mAb/LIF complexes binding immobilized LIFR (Fig. 16B) or gpl30 (Fig. 16C) coated plates.
  • Fig. 22 shows evidence of the modulation of biomarkers that are indicative of the potential mechanism of action of LIF inhibition in tumor biopsy from Subject 0301-004. Data shows results pre-h5D8 treatment compared to on-h5D8 treatment. Fig. 22 shows anti-tumor immunity as percent (%) change in CD68 frequency; % change in CD8 frequency; and % change in Foxp3 frequency.
  • VH-CDR1 immunoglobulin heavy chain complementarity determining region 1
  • VH-CDR2 immunoglobulin heavy chain complementarity determining region 2
  • antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; heavy chain antibodies, single-chain antibody molecules, e.g. single-chain variable region fragments (scFv), nanobodies and multispecific antibodies formed from antibody fragments with separate specificities, such as a bispecific antibody.
  • the antibodies are humanized in such a way as to reduce an individual’s immune response to the antibody.
  • the antibodies may be chimeric, e.g. non-human variable region with human constant region, or CDR grafted, e.g.
  • antibodies are deimmunized after humanization. Deimmunization involves removing or mutating one or more T-cell epitopes in the constant region of the antibody.
  • the antibodies described herein are monoclonal.
  • a “recombinant antibody” is an antibody that comprises an amino acid sequence derived from two different species or, or two different sources, and includes synthetic molecules, for example, an antibody that comprises a non-human CDR and a human framework or constant region.
  • recombinant antibodies of the present invention are produced from a recombinant DNA molecule or synthesized.
  • the ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, Calif., or may be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.
  • Alterations may be made in CDRs, e.g, to improve antibody affinity. Such alterations may be made in CDR encoding codons with a high mutation rate during somatic maturation (See e.g., Chowdhury , Methods Mol. Biol. 207: 179-196 (2008)), and the resulting variant can be tested for binding affinity.
  • Affinity maturation e.g., using error- prone PCR, chain shuffling, randomization of CDRs, or oligonucleotide-directed mutagenesis
  • can be used to improve antibody affinity See e.g., Hoogenboom et al. in Methods in Molecular Biology 178: 1-37 (2001)).
  • the antibodies described herein were generated from rats immunized with DNA encoding human LIF.
  • an antibody that specifically binds LIF comprising a VL-CDR1 at least 80% or 90% identical to that set forth in SEQ ID NO: 9 (RSSQ SLLD SDGHT YLN), a VL-CDR2 at least 80% identical to that set forth in SEQ ID NO: 11 (SVSNLES), and a VL-CDR3 at least 80% or 90% identical to that set forth in SEQ ID NO: 13 (MQATHAPPYT).
  • the one or more human heavy chain framework regions comprises a VH-FR1 amino acid sequence at least about 80%, 90%, 95%, 97%, 98%, or 99% identical to the amino acid sequence set forth in SEQ ID NO: 15, a VH-FR2 amino acid sequence at least about 80%, 90%, 95%, 97%, 98%, or 99% identical to the amino acid sequence set forth in SEQ ID NO: 19, a VH-FR3 amino acid sequence at least about 80%, 90%, 95%, 97%, 98%, or 99% identical to the amino acid sequence set forth in SEQ ID NO: 20, and a VH-FR4 amino acid sequence at least about 80%, 90%, 95%, 97%, 98%, or 99% identical to the amino acid sequence set forth in SEQ ID NO: 24.
  • an antibody that specifically binds LIF comprising a VH-CDR1 amino acid sequence set forth in SEQ ID NO: 1 (GFTFSHAWMH), a VH-CDR2 amino acid sequence set forth in SEQ ID NO: 4 (QIKAKSDDYATYYAESVKG), a VH-CDR3 amino acid sequence set forth in SEQ ID NO: 8 (TSWEWDLDF), a VL-CDR1 amino acid sequence set forth in SEQ ID NO: 9 (RSSQSLLDSDGHTYLN), a VL-CDR2 amino acid sequence set forth in SEQ ID NO: 11 (SVSNLES), and a VL-CDR3 amino acid sequence set forth in SEQ ID NO: 13 (MQATHAPPYT).
  • a recombinant antibody that specifically binds Leukemia Inhibitory Factor (LIF) comprising: a heavy chain complementarity determining region 1 (VH-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 3; a heavy chain complementarity determining region 2 (VH-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 4; a heavy chain complementarity determining region 3 (VH-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 7; a light chain complementarity determining region 1 (VL-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 9; and a light chain complementarity determining region 2 (VL-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 11; and a light chain complementarity determining region 3 (VL-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 13.
  • LIF Leukemia Inhibitory Factor
  • H5D8 and the dosages of h5D8 described herein influence numerous outcomes.
  • the antibodies described herein can reduce the presence of M2
  • a flat dose of h5D8 can be administered from about 225 milligrams to about 2000 milligrams, from about 750 milligrams to about 2000 milligrams, from about 1125 milligrams to about 2000 milligrams, or from about 1500 milligrams to about 2000 milligrams.
  • a flat dose of h5D8 can be administered at about 75 milligrams.
  • a flat dose of h5D8 can be administered at about 225 milligrams.
  • a flat dose of h5D8 can be administered at about 750 milligrams.
  • a flat dose of h5D8 can be administered at about 1125 milligrams.
  • a flat dose of h5D8 can be administered at about 1500 milligrams.
  • a flat dose of h5D8 can be administered at about 2000 milligrams.
  • Antibody-producing cells were isolated and fused with mouse myeloma cells (Ag8) according to standard procedures. Hybridomas producing antibodies specific for LIF were identified by screening in a flow cytometry assay as described above. Cell pellets of positive hybridoma cells were prepared using an RNA protection agent (RNAlater, cat. #AM7020 by ThermoFisher Scientific) and further processed for sequencing of the variable domains of the antibodies.
  • RNA protection agent RNAlater, cat. #AM7020 by ThermoFisher Scientific
  • the humanized 5D8 comprising H2 and L2 was selected for more in-depth analysis due to its high binding affinity and high yield from batch culture.
  • Fig. 2A shows that the humanized clone exhibited increased inhibition of STAT3 phosphorylation (Tyr 705) when a glioma cell line was incubated with human LIF.
  • Fig. 2B shows an experiment with the same set up of Fig. 2A
  • r5D8 The efficacy of r5D8 was evaluated in two other syngeneic tumor models.
  • Human recombinant LIF produced from mammalian cells was from ACROBiosystems (LIF-H52lb); human recombinant OSM produced in mammalian cells was from R & D (8475- OM/CF); and human recombinant OSM produced in E. colt cells was from R & D (295-OM- 050/CF).
  • Octet RED96 The affinity of h5D8 Cl 00 variants to human and mouse LIF was determined by BLI using the Octet RED96 system. h5D8 Cl 00 variants were loaded onto Anti- Human Fc biosensors at 7.5 ug/mL following a 30 second baseline in lx kinetics buffer.

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  • Health & Medical Sciences (AREA)
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  • Engineering & Computer Science (AREA)
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  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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PCT/IB2019/000541 2018-05-14 2019-05-13 Antibodies against lif and dosage forms thereof Ceased WO2019220204A2 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
AU2019269131A AU2019269131B2 (en) 2018-05-14 2019-05-13 Antibodies against LIF and dosage forms thereof
CN201980046565.4A CN112638941A (zh) 2018-05-14 2019-05-13 针对lif的抗体及其剂量形式
SG11202011170YA SG11202011170YA (en) 2018-05-14 2019-05-13 Antibodies against lif and dosage forms thereof
EP19765782.8A EP3794031A2 (en) 2018-05-14 2019-05-13 Antibodies against lif and dosage forms thereof
JP2020563980A JP7536654B2 (ja) 2018-05-14 2019-05-13 Ｌｉｆに対する抗体及びそれらの投与形態
CA3099406A CA3099406A1 (en) 2018-05-14 2019-05-13 Antibodies against lif and dosage forms thereof
EA202092632A EA202092632A1 (ru) 2019-05-03 2019-05-13 Антитела к lif и лекарственные формы на их основе
KR1020207035617A KR20210008514A (ko) 2018-05-14 2019-05-13 Lif에 대한 항체 및 이의 투여 형태
US17/055,279 US20220064279A1 (en) 2018-05-14 2019-05-13 Antibodies against lif and dosage forms thereof
JP2024130558A JP2024160301A (ja) 2018-05-14 2024-08-07 Ｌｉｆに対する抗体及びそれらの投与形態

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EP18382327 2018-05-14
EP18382327.7 2018-05-14
EP18382359.0 2018-05-25
EP18382359 2018-05-25
EP19382208 2019-03-26
EP19382208.7 2019-03-26
EP19382331 2019-05-03
EP19382331.7 2019-05-03

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WO2019220204A3 WO2019220204A3 (en) 2019-12-26

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EP (1) EP3794031A2 (https=)
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KR (1) KR20210008514A (https=)
CN (1) CN112638941A (https=)
AU (1) AU2019269131B2 (https=)
CA (1) CA3099406A1 (https=)
MA (1) MA52021A (https=)
SG (1) SG11202011170YA (https=)
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Cited By (3)

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WO2019243900A3 (en) * 2018-06-18 2020-03-05 Mosaic Biomedicals Slu Combination of lif inhibitors and platinum-based antineoplastic agents for use in treating cancer
WO2021110873A1 (en) * 2019-12-04 2021-06-10 Medimmune Limited Antibodies against lif and uses thereof
US11634485B2 (en) 2019-02-18 2023-04-25 Eli Lilly And Company Therapeutic antibody formulation

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Publication number Priority date Publication date Assignee Title
WO2025149667A1 (en) 2024-01-12 2025-07-17 Pheon Therapeutics Ltd Antibody drug conjugates and uses thereof

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