WO2018007456A1 - Formule d'anticorps. - Google Patents

Formule d'anticorps. Download PDF

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Publication number
WO2018007456A1
WO2018007456A1 PCT/EP2017/066803 EP2017066803W WO2018007456A1 WO 2018007456 A1 WO2018007456 A1 WO 2018007456A1 EP 2017066803 W EP2017066803 W EP 2017066803W WO 2018007456 A1 WO2018007456 A1 WO 2018007456A1
Authority
WO
WIPO (PCT)
Prior art keywords
seq
antibody
amino acid
cxcr5
formulation
Prior art date
Application number
PCT/EP2017/066803
Other languages
English (en)
Inventor
Donny FRANCIS
Ahmed YOUSSEF
Stefaniya KORUEVA
Martina KIRSCH
Original Assignee
Sanofi
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to BR112019000135-2A priority Critical patent/BR112019000135A2/pt
Priority to CA3029642A priority patent/CA3029642A1/fr
Application filed by Sanofi filed Critical Sanofi
Priority to JP2019500292A priority patent/JP7028855B2/ja
Priority to KR1020247015731A priority patent/KR20240073999A/ko
Priority to MX2019000177A priority patent/MX2019000177A/es
Priority to EP17739230.5A priority patent/EP3481420A1/fr
Priority to CN201780054061.8A priority patent/CN109661240B/zh
Priority to CN202211433782.9A priority patent/CN115998858A/zh
Priority to AU2017293103A priority patent/AU2017293103A1/en
Priority to KR1020227033547A priority patent/KR20220137159A/ko
Priority to US16/315,533 priority patent/US11207407B2/en
Priority to RU2019102943A priority patent/RU2769326C2/ru
Priority to SG11201900043TA priority patent/SG11201900043TA/en
Priority to KR1020197003282A priority patent/KR102450280B1/ko
Publication of WO2018007456A1 publication Critical patent/WO2018007456A1/fr
Priority to US17/562,480 priority patent/US20220111048A1/en

Links

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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39591—Stabilisation, fragmentation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • 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
    • C07K2317/90—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

  • the anti-CXCR5 antibody or a fragment thereof includes: (a) a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 1 1 , and a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 12; (b) the amino acid sequences of RSSKSLLHSSGKTYLY (SEQ ID NO: 58), RMSNLAS (SEQ ID NO: 59), MQHLEYPYT (SEQ ID NO: 60), GFSLIDYGVN (SEQ ID NO: 61 ), VIWGDGTTY (SEQ ID NO: 62), and IVY (SEQ ID NO: 63); (c) a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 13, SEQ ID NO: 14, or SEQ ID NO: 15, and a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 16; (d) the amino acid sequences of RSSKSLLHSSGKTYLY (SEQ ID NO: 58), RLSN
  • the amino acid is arginine or methionine.
  • the antibody is an isolated antibody or fragment thereof that specifically binds to the extracellular domain of human CXCR5.
  • the invention provides a lyophilized form of the antibody formulation according to any of the preceding aspects or embodiments.
  • FIG. 12 is a photomicrograph of the cellulose filter of FIG. 1 1 at 200X magnification.
  • analog refers to a polypeptide that possesses a similar or identical function as a CXCR5 polypeptide, a fragment of a CXCR5 polypeptide, a CXCR5 epitope, or an anti-CXCR5 antibody, but does not necessarily comprise a similar or identical amino acid sequence of a CXCR5 polypeptide, a fragment of a CXCR5 polypeptide, a CXCR5 epitope, or an anti-CXCR5 antibody, or possesses a similar or identical structure of a CXCR5 polypeptide, a fragment of a CXCR5 polypeptide, a CXCR5 epitope, or an anti-CXCR5 antibody.
  • a polypeptide that has a similar amino acid sequence refers to a polypeptide that satisfies at least one of the following: (a) a polypeptide having an amino acid sequence that is at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of a CXCR5 polypeptide, a fragment of a CXCR5 polypeptide, a CXCR5 epitope, or an anti-CXCR5 antibody described herein; (b) a polypeptide encoded by a nucleotide sequence that hybridizes under stringent conditions to a nucleotide sequence encoding a CXCR5 polypeptide, a fragment of a CXCR5 polypeptide, a CXCR5 epitope, or an anti-CXCR
  • an "antagonist” or “inhibitor” of CXCR5 refers to a molecule capable of inhibiting one or more biological activities, such as signaling, by CXCR5.
  • antagonists e.g., neutralizing antibodies
  • CXCR5 CXCL13 or other ligands of CXCR5, or a complex of CXCR5 and a ligand thereof, such as CXCL13; amino acid sequence variants or derivatives of CXCR5 or CXCL13 which antagonize the interaction between CXCR5 and a ligand, such as CXCL13; soluble CXCR5, optionally fused to a heterologous molecule such as an immunoglobulin region (e.g., an immunoadhesin); a complex comprising CXCR5 in association with another receptor or biological molecule; synthetic or native sequence peptides which bind to CXCR5; and so on.
  • an immunoglobulin region e.g., an immunoadhesin
  • antibodies include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., antigen binding domains or molecules that contain an antigen-binding site that specifically binds to a CXCR5 antigen (e.g., one or more complementarity determining regions (CDRs) of an anti- CXCR5 antibody).
  • CXCR5 antigen e.g., one or more complementarity determining regions (CDRs) of an anti- CXCR5 antibody.
  • an isolated antibody or fragment thereof that specifically binds to the extracellular domain of human CXCR5 includes the amino acid sequences of RSSKSLLHSSGKTYLY (SEQ ID NO: 58), RLSSLA (SEQ ID NO: 68), MQHLEYPYT (SEQ ID NO: 60), GFSLIDYGVN (SEQ ID NO: 61 ), VIWGDGTTY (SEQ ID NO: 62), and IVY (SEQ ID NO: 63) of U.S. Patent No. 8,647,622.
  • CXCR5 relates to the naturally occurring, known molecule found on lymphocytes, particularly B cells, and particularly na ' ive B cells; to such a molecule isolated from such cells; to such a molecule manufactured recombinantly using known materials and means, and using a nucleic acid encoding a CXCR5; as well as to portions of CXCR5, such as the extracellular (EC) domain, that retain the characteristics and properties relevant to the practice of the instant invention, such as CXCL13 binding.
  • a soluble CXCR5 molecule can consist essentially of the EC domain of CXCR5, which includes, generally, about the first sixty amino acids of the molecule, that is, the amino terminal portion of CXCR5.
  • epitope refers to a localized region on the surface of an antigen, such as a CXCR5 polypeptide, or CXCR5 polypeptide fragment, that is capable of being bound to one or more antigen binding regions of a binding agent, such as an antibody, and that has antigenic or immunogenic activity in an animal, such as a mammal, for example, a human, that is capable of eliciting an immune response.
  • a binding agent such as an antibody
  • An epitope having immunogenic activity is a portion of a polypeptide that elicits an antibody response in an animal.
  • excipients refers to inert substances that are commonly used as a diluent, vehicle, preservative, binder, stabilizing agent, etc. for drugs and includes, but is not limited to, proteins (e.g., serum albumin, etc.), amino acids (e.g., aspartic acid, glutamic acid, lysine, arginine, glycine, histidine, etc.), fatty acids and phospholipids (e.g., alkyl sulfonates, caprylate, etc.), surfactants (e.g., SDS, polysorbate, nonionic surfactant, etc.), saccharides (e.g., sucrose, maltose, trehalose, etc.), and polyols (e.g., mannitol, sorbitol, etc.). See, also, Remington's Pharmaceutical Sciences (1990) Mack Publishing Co., Easton, Pa., which is hereby incorporated by reference in its entirety
  • the antibody When the antibody is recombinantly produced, it is also desirable to be substantially free of culture medium, i.e., culture medium represents less than about 20%, 10%, or 5% of the volume of the protein preparation.
  • culture medium represents less than about 20%, 10%, or 5% of the volume of the protein preparation.
  • the antibody When the antibody is produced by chemical synthesis, in some embodiments, it is substantially free of chemical precursors or other chemicals, i.e., it is separated from chemical precursors or other chemicals that are involved in the synthesis of the protein. Accordingly, such preparations of the antibody have less than about 30%, 20%, 10%, or 5% (by dry weight) of chemical precursors or compounds other than the antibody of interest.
  • anti-CXCR5 antibodies are isolated or purified.
  • an anti-CXCR5 binding agent such as an antibody
  • the term "Kabat numbering" and like terms are recognized in the art and refer to a system of numbering amino acid residues that are more variable (i.e., hypervariable) than other amino acid residues in the heavy and light chain variable regions of an antibody, or an antigen binding portion thereof. (See Kabat et al. (1971 ) Ann. NY Acad. Sci. 190:382-391 and Kabat et al. (1991 )).
  • prevent refers to the total or partial inhibition of the development, recurrence, onset or spread of a CXCR5-mediated disease and/or symptom related thereto, resulting from the administration of a therapy or combination of therapies provided herein (e.g., a combination of prophylactic or therapeutic agents, such as a formulation of the invention).
  • a therapy or combination of therapies provided herein (e.g., a combination of prophylactic or therapeutic agents, such as a formulation of the invention).
  • CXCR5-mediated disease and “CXCR5-mediated disorder” are used interchangeably and refer to any disease that is completely or partially caused by or is the result of CXCR5.
  • CXCR5 is aberrantly (e.g., highly) expressed on the surface of a cell.
  • CXCR5 may be aberrantly upregulated on a particular cell type.
  • normal, aberrant, or excessive cell signaling is caused by binding of CXCR5 to a CXCR5 ligand.
  • the CXCR5 ligand is CXCL13.
  • the CXCR5-mediated disease is rheumatoid arthritis (RA).
  • the terms “specifically binds” or “specifically binding” mean specifically binding to an antigen or a fragment thereof and not specifically binding to other antigens.
  • an antibody that specifically binds to an antigen may bind to other peptides or polypeptides with lower affinity, as determined by, e.g., radioimmunoassays (RIA), enzyme-linked immunosorbent assays (ELISA), BIACORE®, or other assays known in the art.
  • Antibodies or variants or fragments thereof that specifically bind to an antigen may be cross-reactive with related antigens. In some embodiments, antibodies or variants or fragments thereof that specifically bind to an antigen do not cross-react with other antigens.
  • the terms “treat,” “treatment,” and “treating” refer to the reduction or amelioration of the progression, severity, and/or duration of a CXCR5-mediated disease (e.g., rheumatoid arthritis) resulting from the administration of one or more therapies (including, but not limited to, the administration of one or more prophylactic or therapeutic agents, such as a formulation of the invention).
  • a CXCR5-mediated disease e.g., rheumatoid arthritis
  • therapies including, but not limited to, the administration of one or more prophylactic or therapeutic agents, such as a formulation of the invention.
  • CXCR5 refers the reduction or inhibition of the binding of CXCR5 to CXCL13, and/or the inhibition or reduction of one or more symptoms associated with a CXCR5-mediated disease, such as rheumatoid arthritis.
  • the variants will ameliorate, neutralize, or otherwise inhibit CXCR5 biological activity (e.g., the binding of CXCL13 to CXCR5). Determining competition for binding to the target can be done by routine methods known to the skilled person in the art.
  • the variants are human antibodies, and, in some embodiments, are lgG4 molecules.
  • a variant is at least 95%, 96%, 97%, 98%, or 99% identical in amino acid sequence with a contemplated antibody disclosed herein.
  • the term "variant" refers to an antibody that comprises an amino acid sequence that is altered by one or more amino acids compared to the amino acid sequences of the anti-CXCR5 antibody. The variant may have conservative sequence modifications, including amino acid substitutions, modifications, additions, and/or deletions.
  • a pharmaceutical composition comprising a therapeutically effective amount of the antibody or fragment thereof of any one the first, second, or third particular embodiments above and a pharmaceutically acceptable carrier.
  • the formulations of the invention can include a citrate buffer as a buffering agent.
  • Other buffers may also be used.
  • a buffering agent maintains a physiologically suitable pH.
  • a buffering agent enhances isotonicity and chemical stability of the formulation.
  • the citrate buffer is present in the formulations at a concentration from about 0.5 mM to about 50 mM, e.g., about 5 mM to about 15 mM.
  • the formulations of the invention can, optionally, further comprise a surfactant, which is also known as a stabilizing agent.
  • Surfactants/stabilizing agents are chemical compounds that interact and stabilize biological molecules and/or general pharmaceutical excipients in a formulation.
  • surfactants may be used in conjunction with lower temperature storage.
  • Surfactants generally protect the binding agent from air/solution interface induced stresses and solution/surface induced stresses, which may otherwise result in protein aggregation.
  • Surfactants may include, but are not limited to, polysorbates, glycerin, dicarboxylic acids, oxalic acid, succinic acid, fumaric acids, phthalic acids, and combinations thereof. Those skilled in the art are aware that other surfactants, e.g.
  • the surfactant is present in the formulations from about 0.003% to about 0.05% (w/v), about 0.004% to about 0.025% (w/v), or about 0.005% to about 0.02% (w/v), e.g. about 0.005% (w/v).
  • polysorbate 20 may be present in an amount from about 0.001 % to about 0.1% (w/v), about 0.002% to about 0.01 % (w/v), about 0.003% to about 0.008% (w/v), and about 0.004% to about 0.006% (w/v), e.g., about 0.005% (w/v).
  • the invention provides a stable antibody formulation comprising:
  • the invention provides a pharmaceutical unit dosage form comprising a therapeutically effective amount of a formulation of the invention for the treatment of one or more diseases in a subject through administration of the dosage form to the subject.
  • the subject is a human.
  • the human may be an adult or may be an infant.
  • pharmaceutical unit dosage form refers to a physically discrete unit suitable as unitary dosages for the subjects to be treated, each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic/prophylactic effect in association with the required citrate buffer and pH.
  • the formulations are secondarily packaged in a container, such as a cardboard box, that protects the vials from light.
  • Filtration - microscopy Particles were isolated from 5 vials of each batch applying a cellulose nitrate filter with a pore size of 0.45 ⁇ . The obtained particles were analyzed by optical microscopy. The particles were further characterized via IR spectroscopy using the IR microscope Hyperion 2000 at 15x magnification.
  • Flow-imaging microscopy (Micro-flow imaging (MFI), Protein simple) was used to measure the amount of subvisible particles in the protein formulation. As required by pharmacopoeia (USP, Ph. Eur.), particles larger than 10 ⁇ and 25 ⁇ were investigated. Particles were detected by a digital camera.
  • MFI Micro-flow imaging
  • RapID - study The goal of this study was to determine what the Stardust particles consist of. Previous filtration studies were unsuccessful as it was not possible to isolate the particles on filters. RapID offers a solution with gold filters. Here, the DP solution was filtered on a gold filter and then analyzed using FT-IR (FIG. 15) and Raman spectroscopy (FIG. 16). The results showed that in 3 of 5 vials, protein particles were detected. In the other vials, polyethylene has been detected (FIGS. 17 and 18). The samples that contained polyethylene most likely also contained protein as typical absorption peaks for protein above 3000 cm "1 were also seen in FT-IR analysis (FIG. 17).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Microbiology (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Genetics & Genomics (AREA)
  • Mycology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention porte sur une formule d'anticorps à concentration élevée capables d'un stockage stable et à long terme.
PCT/EP2017/066803 2016-07-05 2017-07-05 Formule d'anticorps. WO2018007456A1 (fr)

Priority Applications (15)

Application Number Priority Date Filing Date Title
AU2017293103A AU2017293103A1 (en) 2016-07-05 2017-07-05 Antibody formulations
CN202211433782.9A CN115998858A (zh) 2016-07-05 2017-07-05 抗体制剂
JP2019500292A JP7028855B2 (ja) 2016-07-05 2017-07-05 抗体製剤
CA3029642A CA3029642A1 (fr) 2016-07-05 2017-07-05 Formule d'anticorps.
MX2019000177A MX2019000177A (es) 2016-07-05 2017-07-05 Formulaciones de anticuerpos.
EP17739230.5A EP3481420A1 (fr) 2016-07-05 2017-07-05 Formule d'anticorps.
KR1020227033547A KR20220137159A (ko) 2016-07-05 2017-07-05 항체 제형
BR112019000135-2A BR112019000135A2 (pt) 2016-07-05 2017-07-05 formulações de anticorpo
KR1020247015731A KR20240073999A (ko) 2016-07-05 2017-07-05 항체 제형
CN201780054061.8A CN109661240B (zh) 2016-07-05 2017-07-05 抗体制剂
US16/315,533 US11207407B2 (en) 2016-07-05 2017-07-05 Antibody formulations
RU2019102943A RU2769326C2 (ru) 2016-07-05 2017-07-05 Составы на основе антитела
SG11201900043TA SG11201900043TA (en) 2016-07-05 2017-07-05 Antibody formulations
KR1020197003282A KR102450280B1 (ko) 2016-07-05 2017-07-05 항체 제형
US17/562,480 US20220111048A1 (en) 2016-07-05 2021-12-27 Antibody formulations

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201662358404P 2016-07-05 2016-07-05
US62/358,404 2016-07-05
EP16306090 2016-08-30
EP16306090.8 2016-08-30

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US16/315,533 A-371-Of-International US11207407B2 (en) 2016-07-05 2017-07-05 Antibody formulations
US17/562,480 Division US20220111048A1 (en) 2016-07-05 2021-12-27 Antibody formulations

Publications (1)

Publication Number Publication Date
WO2018007456A1 true WO2018007456A1 (fr) 2018-01-11

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PCT/EP2017/066803 WO2018007456A1 (fr) 2016-07-05 2017-07-05 Formule d'anticorps.

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TW (1) TWI760345B (fr)
WO (1) WO2018007456A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2022519226A (ja) * 2019-01-30 2022-03-22 リジェネロン・ファーマシューティカルズ・インコーポレイテッド 生物学的製剤における可視粒子及び／またはサブビジブル粒子のキャラクタリゼーション方法

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WO2006042333A2 (fr) 2004-10-12 2006-04-20 Xencor, Inc. Prevision et evaluation de l'immunogenicite
WO2009032661A1 (fr) * 2007-08-29 2009-03-12 Sanofi-Aventis Anticorps anti-cxcr5 humanisés, leurs dérivés et leurs utilisations
WO2013148686A2 (fr) * 2012-03-26 2013-10-03 Sanofi Formulations stables d'agent de liaison à igg4
US20140004106A1 (en) * 2012-03-26 2014-01-02 Sanofi Stable igg4 based binding agent formulations

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US5869619A (en) 1991-12-13 1999-02-09 Xoma Corporation Modified antibody variable domains
WO2006042333A2 (fr) 2004-10-12 2006-04-20 Xencor, Inc. Prevision et evaluation de l'immunogenicite
WO2009032661A1 (fr) * 2007-08-29 2009-03-12 Sanofi-Aventis Anticorps anti-cxcr5 humanisés, leurs dérivés et leurs utilisations
US8647622B2 (en) 2007-08-29 2014-02-11 Sanofi Humanized anti-CXCR5 antibodies, derivatives thereof and their use
WO2013148686A2 (fr) * 2012-03-26 2013-10-03 Sanofi Formulations stables d'agent de liaison à igg4
US20140004106A1 (en) * 2012-03-26 2014-01-02 Sanofi Stable igg4 based binding agent formulations

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2022519226A (ja) * 2019-01-30 2022-03-22 リジェネロン・ファーマシューティカルズ・インコーポレイテッド 生物学的製剤における可視粒子及び／またはサブビジブル粒子のキャラクタリゼーション方法
JP7466553B2 (ja) 2019-01-30 2024-04-12 リジェネロン・ファーマシューティカルズ・インコーポレイテッド 生物学的製剤における可視粒子及び／またはサブビジブル粒子のキャラクタリゼーション方法

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