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WO2023138499A1 - Préparation d'anticorps pour reconnaître spécifiquement le récepteur du facteur de stimulation des colonies de granulocytes-macrophages et son utilisation - Google Patents

Préparation d'anticorps pour reconnaître spécifiquement le récepteur du facteur de stimulation des colonies de granulocytes-macrophages et son utilisation Download PDF

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Publication number
WO2023138499A1
WO2023138499A1 PCT/CN2023/072069 CN2023072069W WO2023138499A1 WO 2023138499 A1 WO2023138499 A1 WO 2023138499A1 CN 2023072069 W CN2023072069 W CN 2023072069W WO 2023138499 A1 WO2023138499 A1 WO 2023138499A1
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Prior art keywords
buffer
antibody
sodium chloride
tween
concentration
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Ceased
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PCT/CN2023/072069
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English (en)
Chinese (zh)
Inventor
廖川
海岗
张婷婷
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Staidson Beijing Biopharmaceutical Co Ltd
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Staidson Beijing Biopharmaceutical Co Ltd
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Priority to CN202380009458.0A priority Critical patent/CN116887856A/zh
Publication of WO2023138499A1 publication Critical patent/WO2023138499A1/fr
Anticipated expiration legal-status Critical
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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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • 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

Definitions

  • the invention belongs to the technical field of biomedicine, and in particular relates to an antibody preparation specifically recognizing granulocyte-macrophage colony-stimulating factor receptor alpha (GM-CSFR alpha) and application thereof.
  • GM-CSFR alpha granulocyte-macrophage colony-stimulating factor receptor alpha
  • Granulocyte-macrophage colony-stimulating factor is also known as colony-stimulating factor 2 (CSF2).
  • CSF2 colony-stimulating factor 2
  • GM-CSF is a type I pro-inflammatory cytokine that plays a role in exacerbating inflammatory, respiratory and autoimmune diseases.
  • GM-CSF receptor is a member of the hematopoietic receptor superfamily, which is a heterodimer composed of ⁇ and ⁇ subunits.
  • GM-CSF is capable of binding to the alpha subunit alone with relatively low affinity (Kd 1-5 nM), but not at all to the beta subunit alone.
  • International patent application WO2020/108423A1 discloses an isolated anti-GM-CSFR ⁇ antibody that can treat autoimmune diseases and/or inflammatory disorders or cancers (e.g., rheumatoid arthritis, asthma, myelogenous leukemia) characterized by high expression of GM-CSF and/or GM-CSFR ⁇ and/or abnormal function of GM-CSF/GM-CSFR ⁇ .
  • monoclonal antibody drugs are macromolecular protein drugs. Compared with traditional small molecule drugs, they are prone to aggregation and degradation during storage, which will cause adverse consequences such as increased differences between drug batches and changes in immunogenicity.
  • the present invention finally obtains an anti-GM-CSFR ⁇ antibody preparation with high stability through rational design of preparation prescription and detection.
  • the anti-GM-CSFR ⁇ antibody preparation of the present invention has strong stability, which can ensure good stability of the preparation during preparation, transportation and storage, as well as quality controllability and clinical drug safety.
  • the present invention provides an anti-GM-CSFR ⁇ antibody preparation, the antibody preparation comprising an anti-GM-CSFR ⁇ antibody, a stabilizer, a surfactant, and a buffer, the buffer being a phosphate buffer with a pH of 6.5-7.5, preferably 6.7-7.3, and in some specific embodiments, the pH is 6.7, 6.8, 6.9, 7.0, 7.1, 7.2 or 7.3; more preferably 7.0.
  • the concentration of the buffer is 10mM-30mM; in some specific embodiments, the concentration of the buffer is 10mM, 20mM or 30mM; more preferably 20mM.
  • the concentration of the antibody is 50mg/ml-200mg/ml, preferably, the concentration of the antibody is 50mg/ml-180mg/ml, more preferably 50mg/ml-150mg/ml, more preferably 100mg/m-150mg/ml. In some embodiments, the concentration of the antibody is 50 mg/ml, 75 mg/ml, 100 mg/ml, 125 mg/ml, 150 mg/ml or 180 mg/ml.
  • the stabilizer comprises sodium chloride.
  • the concentration of the sodium chloride is 70mM- 200mM, preferably 100mM-200mM, more preferably 100mM-150mM, further preferably 120mM-150mM.
  • the stabilizer further includes arginine hydrochloride.
  • the concentration of the arginine hydrochloride is 0-50mM, preferably 0-40mM, more preferably 15mM-40mM.
  • the concentration of the sodium chloride is 50mM-150mM, preferably 70mM-150mM; more preferably 70mM-120mM.
  • the stabilizer is:
  • the stabilizer is 100mM, 120mM, 150mM, 180mM or 200mM sodium chloride or arginine hydrochloride; or 15mM arginine hydrochloride and 120mM sodium chloride; or 25mM arginine hydrochloride and 100mM sodium chloride; or 40mM arginine hydrochloride and 70mM sodium chloride; mM sodium chloride; or 75 mM arginine hydrochloride and 75 mM sodium chloride; or 100 mM arginine hydrochloride and 50 mM sodium chloride, or 150 mM arginine hydrochloride and 150 mM sodium chloride.
  • the surfactant is polysorbate; preferably, the polysorbate is Tween-20 or Tween-80.
  • the concentration of the surfactant is 0.05 mg/ml-0.3 mg/ml; preferably, the concentration of the surfactant is 0.1 mg/ml-0.2 mg/ml.
  • the antibody preparation is any of the following preparations:
  • the antibody concentration is 50mg/ml, 75mg/ml, 100mg/ml, 125mg/ml, 150mg/ml or 180mg/ml;
  • the stabilizer is 50mM-150mM (preferably 70mM-120mM) sodium chloride and 0-50mM (preferably 15mM-40mM) arginine hydrochloride, or 100mM-200mM (preferably 120mM- 150mM) of sodium chloride;
  • the buffer is a phosphate buffer of 10mM-30mM; the pH of the buffer is 6.7-7.3;
  • the surfactant is Tween-20 and/or Tween-80 of 0.1mg/ml-0.2mg/ml;
  • the antibody concentration is 50mg/ml-180mg/ml;
  • the stabilizer is 15mM arginine hydrochloride and 120mM sodium chloride, or 25mM arginine hydrochloride and 100mM sodium chloride, or 40mM arginine hydrochloride and 70mM sodium chloride, or 50mM arginine hydrochloride and 100mM sodium chloride, or 100mM, 120mM, 150mM, 180mM or 200mM sodium chloride;
  • the buffer is 10mM-30mM phosphate buffer;
  • the pH of the buffer is 6.7-7.3;
  • the surfactant is Tween-20 and/or Tween-80 of 0.1mg/ml-0.2mg/ml;
  • the antibody concentration is 50mg/ml-180mg/ml;
  • the stabilizer is 50mM-150mM (preferably 70mM-120mM) sodium chloride and 0-50mM (preferably 15mM-40mM) arginine hydrochloride, or 100mM-200mM (preferably 120mM-150mM) sodium chloride;
  • the buffer is 10mM, 20mM, 30mM M phosphate buffer;
  • the pH value of the buffer is 6.7-7.3;
  • the surfactant is Tween-20 and/or Tween-80 of 0.1mg/ml-0.2mg/ml;
  • the antibody concentration is 50mg/ml-180mg/ml;
  • the stabilizer is 50mM-150mM (preferably 70mM-120mM) sodium chloride and 0-50mM (preferably 15mM-40mM) arginine hydrochloride, or 100mM-200mM (preferably 120mM-150mM) sodium chloride;
  • the buffer is 10mM-30mM phosphate buffer solution;
  • the pH value of the buffer is 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3;
  • the surfactant is Tween-20 and/or Tween-80 of 0.1mg/ml-0.2mg/ml;
  • the antibody concentration is 50mg/ml-180mg/ml; the stabilizer is 50mM-150mM (preferably 70mM-120mM) Sodium chloride and 0-50mM (preferably 15mM-40mM) arginine hydrochloride, or 100mM-200mM (preferably 120mM-150mM) sodium chloride; the buffer is 10mM-30mM phosphate buffer; the pH of the buffer is 6.7-7.3; the surfactant is 0.1mg/ml, 0.15mg/ml, 0.2mg/ml Tween-2 0 or Tween-80;
  • the antibody concentration is 50mg/ml-180mg/ml; the stabilizer is 100mM-200mM (preferably 120mM-150mM) sodium chloride; the buffer is 10mM-30mM phosphate buffer; the pH of the buffer is 6.7-7.3; the surfactant is 0.1mg/ml-0.2mg/ml Tween-20 or Tween-80;
  • the antibody concentration is 50mg/ml-180mg/ml; the stabilizer is 50mM-150mM (preferably 70mM-120mM) sodium chloride and 0-50mM (preferably 15mM-45mM) arginine hydrochloride; the buffer is 10mM-30mM phosphate buffer; the pH of the buffer is 6.7-7.3; the surfactant is 0.1mg/ml-0. 2 mg/ml of Tween-20 or Tween-80.
  • the antibody preparation is any of the following preparations:
  • the antibody concentration is 100mg/ml;
  • the stabilizer is 25mM arginine hydrochloride and 100mM sodium chloride;
  • the buffer is 20mM phosphate buffer;
  • the pH of the buffer is 6.7 or 7.0 or 7.3;
  • the surfactant is Tween-20 or Tween-80 of 0.1mg/ml or 0.2mg/ml;
  • the antibody concentration is 100mg/ml;
  • the stabilizer is 100mM or 120mM or 200mM sodium chloride;
  • the buffer is 20mM phosphate buffer;
  • the pH of the buffer is 7.0;
  • the surfactant is Tween-20 or Tween-80 of 0.1mg/ml or 0.2mg/ml;
  • the antibody concentration is 100mg/ml;
  • the stabilizer is 50mM arginine hydrochloride and 70mM sodium chloride;
  • the buffer is 20mM phosphate buffer;
  • the pH of the buffer is 7.0;
  • the surfactant is Tween-20 or Tween-80 of 0.1mg/ml or 0.2mg/ml;
  • the antibody concentration is 150mg/ml; the stabilizer is 15mM arginine hydrochloride and 120mM sodium chloride; the buffer is 20mM phosphate buffer; the pH of the buffer is 7.0; the surfactant is 0.1mg/ml or 0.2mg/ml of Tween-20 or Tween-80.
  • the antibody preparation may further comprise antioxidants and/or preservatives.
  • the antioxidant includes but not limited to ascorbic acid and/or methionine;
  • the preservative includes but not limited to octadecyl dimethyl benzyl ammonium chloride, hexamethyl ammonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butanol or benzyl alcohol, alkyl p-hydroxybenzoate, etc.
  • the antibody preparation is a liquid preparation or a powder for injection.
  • the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1 or 2, and a light chain comprising the amino acid sequence of SEQ ID NO: 3.
  • the present invention discloses the use of the antibody preparation in the preparation of medicines for treating diseases.
  • the disease comprises an autoimmune disease, an inflammatory disorder, or cancer; preferably, the disease is rheumatoid arthritis, asthma, or myelogenous leukemia.
  • the anti-GM-CSFR ⁇ antibody preparation provided by the present invention has the following excellent effects:
  • the present invention screens out the best buffer system for anti-GM-CSFR ⁇ antibody. Compared with other buffer systems, the phosphate buffer system with pH6.5-7.5 The flushing solution can make the anti-GM-CSFR ⁇ antibody preparation have low turbidity, low viscosity, optimal thermal stability (Tm) and good uniformity.
  • the present invention uses sodium chloride and/or arginine hydrochloride as a stabilizer, especially sodium chloride combined with lower concentration of arginine hydrochloride (0-50mM) as a stabilizer or 100mM-200mM sodium chloride as a stabilizer, which can significantly reduce the formation of aggregates in antibody preparations, slow down the change of charge heterogeneity, prevent the formation and aggregation of acidic substances, and maintain good stability for antibody preparations.
  • the anti-GM-CSFR ⁇ antibody preparation of the present invention has strong stability, which can maintain good stability of the preparation during preparation, transportation and storage, and ensure quality controllability and clinical drug safety.
  • reagents used in the following examples were prepared by conventional methods or obtained from commercial sources; the experimental methods used, unless otherwise specified, were conventional methods; the materials and instruments used, if not otherwise specified, were obtained from commercial sources.
  • the anti-GM-CSFR ⁇ antibody is an antibody that binds to granulocyte-macrophage colony-stimulating factor receptor ⁇ (GM-CSFR ⁇ ).
  • GM-CSFR ⁇ granulocyte-macrophage colony-stimulating factor receptor ⁇
  • E35-1 used in the examples of the present invention is disclosed in the international patent application WO2020/108423A1, the disclosure of which is incorporated herein by reference.
  • Embodiment 1 screening the buffer system of anti-GM-CSFR ⁇ antibody preparation
  • the GM-CSFR ⁇ antibody E35-1 (without PS20) was dialyzed into the buffer system, and excipients (sodium chloride, mannitol, sucrose or sorbitol) and PS20 were added, the Tm value was detected by differential scanning fluorescence (DSF), and the turbidity was measured by nephelometry.
  • Tm value detection results are shown in Table 2. It can be seen from Table 2 that in buffer systems with different pH ranges, the Tm values of the tested antibodies are different. Antibody samples in phosphate buffer at pH 7.0 had a higher Tm (higher than 66°C), indicating that the anti-GM-CSFR ⁇ antibody had significantly higher thermal stability at this pH and buffer system.
  • the pH range of three different buffer systems (100mM histidine hydrochloride, 20mM phosphate and 200mM Tris hydrochloride) was adjusted within the range of 6.8-7.2, and the Tm value was further detected by DSF method.
  • the antibody sample in the phosphate buffer has a higher TM value compared to other commonly used cushioning systems (histidine and Tris hydrochloric acid).
  • the TM value of the antibody sample in the phosphate buffer in phosphate buffer is basically unchanged under different pH values.
  • Anti-GM-CSFR ⁇ antibody the pH value of about 6.8-7.2 phosphate buffer has a better stable effect than other commonly used buffer.
  • the GM-CSFR ⁇ antibody E35-1 (buffer system is 100mM histidine at pH 7.0 and 20mM phosphate buffer at pH 7.0) was concentrated to a high concentration (50mg/ml-150mg/ml), and its pH value and viscosity were measured.
  • the 20mM phosphate buffer system can well maintain the pH value at about 7.0; while in other buffer systems (for example, 100mM histidine buffer), the pH value decreases with the increase of the antibody concentration, and the pH value of the solution cannot be maintained stably.
  • the viscosity of the antibody at 50mg/ml and 100mg/ml was lower than 2.0cP, meeting the requirements for subcutaneous injection, but in contrast, the viscosity of the antibody in the 20mM phosphate buffer system was lower than that in the 100mM histidine hydrochloride buffer system.
  • the hydrodynamic radius of antibody molecules was examined using dynamic light scattering to assess the uniformity of antibody particle size.
  • the anti-GM-CSFR ⁇ antibody preparation in the 20mM phosphate buffer with a pH value of 7.0, compared with other buffer systems, the anti-GM-CSFR ⁇ antibody preparation has better turbidity and viscosity, and has the best thermal stability (Tm) and good uniformity.
  • Embodiment 2 the screening of tensio-active agent
  • Oscillating conditions 200rpm, at room temperature, and samples were collected on the 1st, 3rd, and 5th days to detect antibody concentration, turbidity, and aggregate characteristics.
  • the aggregate characteristics were detected by SEC method.
  • Microfluidic imager was used to quantify the particles below visible light.
  • the F1 sample had a relatively high number of particles (5145 particles/ml for >10 ⁇ m particles and 303 particles/ml for >25 ⁇ m particles) when placed in the vial on day 0, and the number increased beyond the detection range after 3 days of shaking; the samples of F2-F5 still maintained a low number of particles after shaking for 5 days (all particles >10 ⁇ m were below 642 particles/ml, and particles >25 ⁇ m less than 75/ml). There were no significant differences among groups F2-F5.
  • Antibody preparations were frozen at -70°C, thawed at room temperature, and mixed by pipette before thawing. Samples were collected after 3 and 5 cycles to detect antibody concentration, turbidity, and aggregate properties, which were detected by SEC.
  • the test results showed that after repeated freezing and thawing five times, the antibody concentration, turbidity and HWM% of the F1 group increased compared with those without freezing and thawing, and the antibody concentration, turbidity and HWM% of the F2-F5 group did not change compared with those without freezing and thawing, and there was no significant difference between the F2-F5 groups (results not shown).
  • PS20 and PS80 added at 0.01%-0.02% have good protective effects against GM-CSFR ⁇ antibody, and there is no significant difference between them.
  • the GM-CSFR ⁇ antibodies (E35-1 and E35-2) were dialyzed into pH7.3 and pH6.7 buffers, respectively, and corresponding adjuvants were added according to Table 7. Place it at 45°C, collect samples after 1, 2, 3, and 4 weeks, and detect the concentration, turbidity, aggregation characteristics, and charge heterogeneity of antibody preparations to evaluate the stability of different antibody preparations. Among them, the aggregation characteristics were detected by HPLC-SEC method, and the charge heterogeneity was detected by iIEF method.
  • the antibody concentration of each group had no significant change (results not shown), and the turbidity tended to increase slightly.
  • the F8 (arginine hydrochloride) group and the F9 (sodium chloride) group had the least increase in turbidity value compared to 0 weeks, only about 0.02, and the turbidity of the F8 (arginine hydrochloride) group and the F9 (sodium chloride) group was the lowest at 4 weeks, especially the turbidity value of the F9 group was only 0.297, indicating that the antibody stability of the F9 group was the highest.
  • the detection results of HPLC-SEC are shown in Table 8.
  • the aggregates in each group of preparations have an increasing trend, and the main peak has a decreasing trend.
  • the F8 (arginine hydrochloride) and F9 (sodium chloride) groups especially the F9 group aggregates had the slowest increase rate and the slowest main peak decrease rate.
  • the main peaks of both F8 and F9 were greater than 95%, in contrast, the proportions of the main peaks in the other groups had dropped below 95%.
  • the antibody concentration of each group had no significant change, and the turbidity showed a slight upward trend.
  • the F8 (arginine hydrochloride) group and the F9 (sodium chloride) group had the least increase in turbidity value compared with the 0-week period, which was only about 0.03.
  • the F8 (arginine hydrochloride) group and the F9 (sodium chloride) group had the lowest turbidity values, especially the F9 group. The turbidity value was only 0.269, indicating that the F9 group had the highest antibody stability.
  • the stabilizer is arginine hydrochloride and sodium chloride or the stabilizer is sodium chloride, which can significantly reduce the formation of aggregation, slow down the change of charge heterogeneity, and prevent the formation and aggregation of acidic substances.
  • the stabilizer is sodium chloride, and its stabilizing effect is more significant.
  • Embodiment 4 evaluate the combined effect of different stabilizers
  • samples were collected after 1, 2, 3 and 4 weeks, and the concentration, turbidity, aggregation characteristics, degradation characteristics, charge heterogeneity, and antigen binding ability of the E35-1 antibody preparation were detected.
  • the polymer characteristics were detected by HPLC-SEC method
  • the degradation characteristics were detected by NR-CE-SDS and R-CE-SDS methods
  • the charge heterogeneity was detected by iIEF method.
  • the osmotic pressure of each group of preparations is shown in Table 11, and the osmotic pressure of A2, A3, A5-A7 is between 300mOsm/kg-400mOsm/kg.
  • the result of turbidity test shows, when compared with 0 weeks, after 4 weeks, in the control group A1 and the A3 group that only added sodium chloride, the turbidity of each preparation has no obvious change, and the turbidity value of preparation in each group that adds arginine hydrochloride all increases to varying degrees: A5 and A7 groups (the addition amount of arginine hydrochloride is at 50mM-75mM) after 4 weeks, turbidity increases respectively 0.187 and 0.204, A2, A4, A6 (addition of arginine hydrochloride The amount is 100mM-150mM) group of preparations, after 4 weeks, the turbidity increase range is between 0.25-0.27.
  • Embodiment 5 Stability experiment of anti-GM-CSFR ⁇ antibody preparation
  • Table 16 shows the freeze-thaw results of each preparation of the E35-1 antibody. After 5 freeze-thaw cycles, the protein concentration was only slightly reduced (102.88mg/mL vs 100.25mg/mL) compared to the non-freeze-thaw preparation. However, the detection results of HPLC-SEC showed that the aggregate remained basically unchanged. The number of particles below visibility has been increased.
  • the E35-2 antibody preparation also showed good stability: after 5 times of freezing and thawing, the protein concentration was only slightly decreased compared to the non-freezing and thawing preparation (results not shown). However, the detection of aggregates by HPLC-SEC remained basically unchanged. Slightly increased particle count below visibility.
  • the antibody preparation of the T1 group (20mM PB, 25mM arginine hydrochloride, 100mM sodium chloride, pH 7) was filtered 5 times through a Meissner SteriLUX hydrophilic PVDF 0.2 filter, and the antibody concentration was detected after each filtration.
  • Table 17 shows the results of filtration experiments of various preparations of the E35-1 antibody. After 5 times of filtration, the concentration of the antibody did not change significantly compared to that without filtration.
  • the HPLC-SEC results are shown in Table 18. Compared with the 0th week, the aggregation degree of antibodies in each group showed a slight increase trend after 4 weeks. However, the main peaks in the T1-T3 and T5-T6 groups only decreased by 0.84%-1.29%, and the aggregates increased by 0.84%-1.29%; while the main peaks in the T4 and T7-T8 groups decreased by 1.39%-1.43%, and the aggregates increased by 1.34%-1.41%. In contrast, the stability of the antibody preparations in the T1-T3 group was better than that in the T4, T7-T8 group preparations.
  • the results of cGE are shown in Table 19.
  • the results showed that, compared with week 0, the main peak and fragments changed after 4 weeks, the main peak had a slight decreasing trend, and the fragments had a slight increasing trend.
  • the T1 non-reducing main peak decreased by 3.6%
  • the reducing main peak decreased by 1.4%
  • the T2-T3, T5-T6 non-reducing main peak decreased by 4.2%-4.5%
  • the T4, T7-T8 non-reducing main peak decreased by 4.8%-5.0%.
  • the above results further confirm that the stability of the antibody preparations in the T1-T3 group is better than that in the T4 and T7-T8 groups.
  • Table 20 shows the results of the binding ability of the antibody to the antigen. Compared with the 0 week, after 4 weeks of storage, the binding ability of all preparations to the antigen remained basically unchanged.
  • the T1 non-reducing main peak decreased by 3.4%
  • the reducing main peak decreased by 1.5%
  • the T2-T3, T5-T6 non-reducing main peak decreased by 4.2%-4.6%
  • the T4, T7-T8 non-reducing main peak decreased by more than 5.0%.
  • the stability of the antibody preparations of the T1-T3 group is better than that of the T5-T6 group preparations, and even better than that of the T4 and T7-T8 group preparations.
  • the anti-GM-CSFR ⁇ antibody preparation of the present invention is stable within 5 cycles of freezing and thawing; there is no obvious antibody loss after 5 times of filtration; the antibody is slightly degraded under high temperature conditions, but not obvious.
  • the combination of arginine hydrochloride and sodium chloride with a concentration lower than 50 mM as a stabilizer has a stronger protective effect on the antibody than sodium chloride alone as a stabilizer, and has a more excellent effect.
  • E35-1 and E35-2 antibody preparations T1 group and T4 group were prepared according to the recipe in Example 5.
  • the stability of the antibody preparation was tested under long-term storage conditions (5 ⁇ 3°C for 0 days, 1 month, 3 months, and 6 months).
  • Table 21 shows the stability results of E35-1 antibody preparations under long-term storage conditions. Compared with 0 months, after 6 months, the indicators of E35-1 antibody preparations in groups T1 and T4 remained basically unchanged.
  • E35-2 antibody preparations also showed good stability under long-term storage conditions. Compared with 0 months, after 6 months, the indicators of E35-2 antibody preparations in groups T1 and T4 remained basically unchanged.
  • E35-1 and E35-2 antibody preparations were tested under long-term accelerated conditions (25°C ⁇ 2°C for 0 days, 1 month, 3 months, and 6 months).
  • Table 22 shows the stability results of E35-1 antibody preparations under accelerated conditions. Compared with 0 months, at 6 months, the E35-1 antibody preparations only showed a slight decrease in the main peak, a slight increase in the acid peak, and other indicators remained basically unchanged.
  • the E35-2 antibody preparation also showed good stability under long-term accelerated conditions. Compared with 0 months, after 6 months, the E35-2 antibody preparation only showed a slight decrease in the main peak, a slight increase in the acid peak, and other indicators remained basically unchanged.
  • the anti-GM-CSFR ⁇ antibody preparation of the present invention has high stability under long-term storage and long-term accelerated conditions, which can ensure good stability of the preparation during preparation, transportation and storage, and ensure the safety and quality controllability of clinical medication.

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Abstract

Préparation d'anticorps anti-GM-CSFRα. La préparation contient un anticorps anti-GM-CSFRα, un stabilisant, un tensioactif et un tampon, le tampon étant un tampon phosphate à une valeur de pH de 6,5 à 7,5. La préparation d'anticorps anti-GM-CSFRα présente une bonne stabilité pendant la préparation, le transport et le stockage, et assure une contrôlabilité de qualité et une sécurité de médicament clinique.
PCT/CN2023/072069 2022-01-20 2023-01-13 Préparation d'anticorps pour reconnaître spécifiquement le récepteur du facteur de stimulation des colonies de granulocytes-macrophages et son utilisation Ceased WO2023138499A1 (fr)

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CN202380009458.0A CN116887856A (zh) 2022-01-20 2023-01-13 一种特异性地识别粒细胞-巨噬细胞集落刺激因子受体的抗体制剂及其应用

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WO2019070680A2 (fr) * 2017-10-02 2019-04-11 Humanigen, Inc. Méthodes de traitement de la toxicité associée aux immunothérapies utilisant un antagoniste du gm-csf
CN113164520A (zh) * 2018-09-10 2021-07-23 赫曼尼根公司 使用gm-csf拮抗剂治疗免疫疗法相关毒性的方法
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CN103641915A (zh) * 2006-03-27 2014-03-19 医学免疫有限公司 Gm-csf受体结合元件
CN101605547A (zh) * 2006-11-21 2009-12-16 卡罗拜奥斯制药公司 使用gm-csf拮抗剂治疗慢性炎症疾病的方法
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WO2019070680A2 (fr) * 2017-10-02 2019-04-11 Humanigen, Inc. Méthodes de traitement de la toxicité associée aux immunothérapies utilisant un antagoniste du gm-csf
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