WO2021147642A1 - Procédés, modèles et systèmes liés à l'immunogénicité d'anticorps - Google Patents

Procédés, modèles et systèmes liés à l'immunogénicité d'anticorps Download PDF

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WO2021147642A1
WO2021147642A1 PCT/CN2020/141999 CN2020141999W WO2021147642A1 WO 2021147642 A1 WO2021147642 A1 WO 2021147642A1 CN 2020141999 W CN2020141999 W CN 2020141999W WO 2021147642 A1 WO2021147642 A1 WO 2021147642A1
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antibody
loop
cdr regions
immunogenicity
cdrh3
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PCT/CN2020/141999
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Shide LIANG
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Bio-Thera Solutions, Ltd.
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6854—Immunoglobulins
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
    • C07K16/4283—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an allotypic or isotypic determinant on Ig
    • 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]

Definitions

  • the present disclosure belongs to the field of biopharmaceutical and relates to methods of selecting a candidate therapeutic antibody with low immunogenicity, methods of producing an antibody with low immunogenicity, methods of reducing immunogenicity of an antibody, methods of identifying an antibody with low immunogenicity, methods of predicting antibody immunogenicity, systems for identifying or predicting antibody immunogenicity, and antibodies designed or produced using the methods or systems.
  • therapeutic proteins including monoclonal antibodies, coagulation factors, replacement enzymes, fusion proteins, hormones, growth factors, and plasma proteins are now a fast growing segment of the pharmaceutical industry. These approved therapeutic proteins are indicated for a wide variety of areas such as cancers, autoimmunity/inflammation, exposure to infectious agents, and genetic disorders. The rapid advances in biomedical science and technology make it possible to address the unmet needs with new therapeutic proteins.
  • biopharmaceuticals can bind the flat surface of a protein with high specificity to interfere in vivo processes and restore previously untreatable conditions.
  • unwanted immune responses such as generation of anti-drug antibody (ADA)
  • ADA anti-drug antibody
  • the immunogenicity against therapeutic proteins can be generated in both T cell dependent and T cell independent pathways.
  • Antibodies generated from T cell dependent pathway have a higher affinity than those generated from T cell independent activation and appear to play a critical role in the development of antibody responses to biologic therapeutics.
  • T cells are activated by the recognition of linear antigenic peptides derived from the therapeutic proteins, called T cell epitope. The activated T cells then stimulate B cells to generate ADAs against the therapeutic protein.
  • T cell epitopes So far computational prediction of T cell epitopes achieved significant progress. Numerous prediction algorithms have been developed and an AUC (area under curve) value of 0.786 was obtained for a large test set by consensus approach. Unlike molecules recognizing T cell epitopes, antibodies bind a conformational epitope on the protein surface, called B cell epitope. The existing tools predict the sequence-discontinuous B cell epitope based on the physiochemical properties of a protein structure and the performance is far from ideal with an accuracy slightly better than random. More frequently, T cell epitopes were predicted and deleted for biotherapeutic deimmunization, partly due to the difficulty of direct prediction of B cell epitopes.
  • the method comprises selecting an antibody having a large cavity volume at the complementarity-determining regions (CDR) of the antibody, having a significantly hydrophobic surface area at the heavy-chain complementarity-determining region 3 (CDRH3) loop of the antibody, or containing one or more glycine residues at the ⁇ turn of heavy-chain complementarity-determining region 2 (CDRH2) loop of the antibody.
  • CDR complementarity-determining regions
  • the candidate therapeutic antibody with low immunogenicity comprises two or more features selected from the list: having one or more large cavities at the CDR regions of the antibody, having a significantly hydrophobic surface area at the CDRH3 loop of the antibody, or containing one or more glycine residues at the ⁇ turn of CDRH2 loop of the antibody.
  • the candidate therapeutic antibody with low immunogenicity has one or more large cavities at the CDR regions, has a significantly hydrophobic CDRH3 loop, and contains one or more glycine residues at the ⁇ turn of CDRH2 loop.
  • the sum of cavity volumes at the CDR regions is about or more. In some embodiments, the sum of cavity volumes at the CDR regions is about to about For example, the sum of cavity volumes at the CDR regions is about or a number or a range between any two of these values. In some embodiments, the sum of cavity volumes at the CDR regions is about or more. In some embodiments, the sum of cavity volumes at the CDR regions is about or more. In some embodiments, the sum of cavity volumes at the CDR regions is about or more.
  • the significantly hydrophobic CDRH3 loop has a ratio of hydrophobic surface to total surface for the CDRH3 loop of about 63%or more. In some embodiments, the significantly hydrophobic CDRH3 loop has a ratio of hydrophobic surface to total surface for the CDRH3 loop of about 63%to about 80%. For example, the ratio of hydrophobic surface to total surface for the CDRH3 loop is about 63%, 64%, 65%, 67%, 68%, 69%, 70%, 74%, 80%, or a number or a range between any two of these values. In some embodiments, the ratio of hydrophobic surface to total surface for the CDRH3 loop is about 67%or more. In some embodiments, the CDRH3 hydrophobic surface area is about or a number or a range between any two of these values.
  • the ⁇ turn of CDRH2 loop (heavy chain (VH) 52-56) has at least one glycine residue.
  • the ⁇ turn of CDRH2 loop (VH 52-56) has one glycine residue, two glycine residues, three glycine residues, or four glycine residues.
  • the ⁇ turn of CDRH2 loop (VH 52-56) has at least two glycine residues.
  • the method comprises: increasing the cavity volume at the CDR regions of the antibody, increasing the hydrophobic surface area at the CDRH3 loop of the antibody, or introducing one or more glycine residues at the ⁇ turn of CDRH2 loop of the antibody.
  • the method comprises two or more of the following: increasing the cavity volume at the CDR regions of the antibody, increasing the hydrophobic surface area at the CDRH3 loop of the antibody, or introducing one or more glycine residues at the ⁇ turn of CDRH2 loop of the antibody. In some embodiments, the method comprises: increasing the cavity volume at the CDR regions of the antibody, increasing the hydrophobic surface area at the CDRH3 loop of the antibody, and introducing one or more glycine residues at the ⁇ turn of CDRH2 loop of the antibody.
  • the sum of cavity volumes at the CDR regions is increased to about or more. In some embodiments, the sum of cavity volumes at the CDR regions is increased to about to about For example, the sum of cavity volumes at the CDR regions is increased about or a number or a range between any two of these values. In some embodiments, the sum of cavity volumes at the CDR regions is increased to about or more. In some embodiments, the sum of cavity volumes at the CDR regions is increased to about or more. In some embodiments, the sum of cavity volumes at the CDR regions is increased to about or more.
  • the ratio of hydrophobic surface to total surface for the CDRH3 loop is increased to about 63%or more. In some embodiments, the ratio of hydrophobic surface to total surface for the CDRH3 loop is increased to about 63%to about 80%. For example, the ratio of hydrophobic surface to total surface for the CDRH3 loop is increased to about 63%, 64%, 65%, 67%, 68%, 69%, 70%, 74%, 80%, or a number or a range between any two of these values. In some embodiments, the ratio of hydrophobic surface to total surface for the CDRH3 loop is increased to about 67%or more. In some embodiments, the CDRH3 hydrophobic surface area is increased to about or a number or a range between any two of these values.
  • the ⁇ turn of CDRH2 loop (VH 52-56) has at least one glycine residue.
  • the ⁇ turn of CDRH2 loop (VH 52-56) has one glycine residue, two glycine residues, three glycine residues, or four glycine residues.
  • the ⁇ turn of CDRH2 loop (VH 52-56) has at least two glycine residues.
  • the method comprises: increasing the cavity volume at the CDR regions of the antibody, increasing the hydrophobic surface area at the CDRH3 loop of the antibody, or adding one or more glycine residues at the ⁇ turn of CDRH2 loop of the antibody.
  • the method comprises two or more of the following: increasing the cavity volume at the CDR regions of the antibody, increasing the hydrophobic surface area at the CDRH3 loop of the antibody, or adding one or more glycine residues at the ⁇ turn of CDRH2 loop of the antibody. In some embodiments, the method comprises: increasing the cavity volume at the CDR regions of the antibody, increasing the hydrophobic surface area at the CDRH3 loop of the antibody, and adding one or more glycine residues at the ⁇ turn of CDRH2 loop of the antibody.
  • the sum of cavity volumes at the CDR regions is increased to about or more. In some embodiments, the sum of cavity volumes at the CDR regions is increased to about to about For example, the sum of cavity volumes at the CDR regions is increased to about or a number or a range between any two of these values. In some embodiments, the sum of cavity volumes at the CDR regions is increased to about or more. In some embodiments, the sum of cavity volumes at the CDR regions is increased to about or more. In some embodiments, the sum of cavity volumes at the CDR regions is increased to about or more.
  • the ratio of hydrophobic surface to total surface for the CDRH3 loop is increased to about 63%or more. In some embodiments, the ratio of hydrophobic surface to total surface for the CDRH3 loop is increased to about 63%to about 80%. For example, the ratio of hydrophobic surface to total surface for the CDRH3 loop is increased to about 63%, 64%, 65%, 67%, 68%, 69%, 70%, 74%, 80%, or a number or a range between any two of these values. In some embodiments, the ratio of hydrophobic surface to total surface for the CDRH3 loop is increased to about 67%or more. In some embodiments, the CDRH3 hydrophobic surface area is increased to about or a number or a range between any two of these values.
  • the ⁇ turn of CDRH2 loop (VH 52-56) has at least one glycine residue.
  • the ⁇ turn of CDRH2 loop (VH 52-56) has one glycine residue, two glycine residues, three glycine residues, or four glycine residues.
  • the ⁇ turn of CDRH2 loop (VH 52-56) has at least two glycine residues.
  • an antibody produced by the method described herein comprises two or more features from the list: having one or more large cavities at the CDR regions, having a significantly hydrophobic CDRH3 loop, and containing one or more glycine residues at the ⁇ turn of CDRH2 loop.
  • the antibody is antibody that has not been previously made.
  • a method of producing an antibody with low immunogenicity comprising producing an antibody having one or more large cavities at the CDR regions, a significantly hydrophobic surface area at the CDRH3 loop, and/or one or more glycine residues at the ⁇ turn of CDRH2 loop of the antibody.
  • the antibody is antibody that has not been previously made.
  • the method of producing an antibody with low immunogenicity comprises designing an antibody having one or more large cavities at the CDR regions, a significantly hydrophobic surface area at the CDRH3 loop, and/or one or more glycine residues at the ⁇ turn of CDRH2 loop of the antibody, and producing the antibody.
  • designing the antibody can be done by the methods or systems described herein.
  • the antibody has one or more large cavities at the CDR regions, has a significantly hydrophobic CDRH3 loop, and contains one or more glycine residues at the ⁇ turn of CDRH2 loop.
  • the sum of cavity volumes at the CDR regions is about or more. In some embodiments, the sum of cavity volumes at the CDR regions is about to For example, the sum of cavity volumes at the CDR regions is about or a number or a range between any two of these values. In some embodiments, the sum of cavity volumes at the CDR regions is about or more. In some embodiments, the sum of cavity volumes at the CDR regions is about or more. In some embodiments, the sum of cavity volumes at the CDR regions is about or more.
  • the significantly hydrophobic CDRH3 loop has a ratio of hydrophobic surface to total surface for the CDRH3 loop of about 63%or more. In some embodiments, the significantly hydrophobic CDRH3 loop has a ratio of hydrophobic surface to total surface for the CDRH3 loop of about 63%to 80%. For example, the ratio of hydrophobic surface to total surface for the CDRH3 loop is about 63%, 64%, 65%, 67%, 68%, 69%, 70%, 74%, 80%, or a number or a range between any two of these values. In some embodiments, the ratio of hydrophobic surface to total surface for the CDRH3 loop is about 67%or more. In some embodiments, the CDRH3 hydrophobic surface area is about or a number or a range between any two of these values.
  • the ⁇ turn of CDRH2 loop (VH 52-56) has at least one glycine residue.
  • the ⁇ turn of CDRH2 loop (VH 52-56) has one glycine residue, two glycine residues, three glycine residues, or four glycine residues.
  • the ⁇ turn of CDRH2 loop (VH 52-56) has at least two glycine residues.
  • compositions comprising the antibody, optionally together with a suitable carrier, excipient or diluent.
  • the method comprises analyzing two or more features selected from the list: cavity volume at the CDR regions of the antibody, hydrophobicity of CDRH3 loop of the antibody, or information of the presence/absence of glycine residues at CDRH2 ⁇ turn of the antibody; wherein if the antibody has two or more of one or more large cavities at the CDR regions, a significantly hydrophobic CDRH3 loop, or one or more glycine residues at the ⁇ turn of CDRH2 loop, the antibody is identified as having low immunogenicity or likely to have low immunogenicity.
  • the method comprises analyzing two or more features selected from the list: cavity volume at the CDR regions of the antibody, hydrophobicity of CDRH3 loop of the antibody, or information of the presence/absence of glycine residues at CDRH2 ⁇ turn of the antibody; wherein if the antibody has two or more of one or more large cavities at the CDR regions, a significantly hydrophobic CDRH3 loop, or one or more glycine residues at the ⁇ turn of CDRH2 loop, the antibody is predicted as having low immunogenicity or likely to have low immunogenicity.
  • the method comprises analyzing two features: cavity volume at the CDR regions of the antibody and hydrophobicity of CDRH3 loop of the antibody; wherein if the antibody has one or more large cavities at the CDR regions and a significantly hydrophobic CDRH3 loop, the antibody is identified or predicted as having low immunogenicity or likely to have low immunogenicity.
  • the method comprises analyzing two features: hydrophobicity of CDRH3 loop of the antibody and information of the presence/absence of glycine residues at CDRH2 ⁇ turn of the antibody; wherein if the antibody has a significantly hydrophobic CDRH3 loop and contains one or more glycine residues at the ⁇ turn of CDRH2 loop, the antibody is identified or predicted as having low immunogenicity or likely to have low immunogenicity.
  • the method comprises analyzing three features: cavity volume at the CDR regions of the antibody, hydrophobicity of CDRH3 loop of the antibody and information of the presence/absence of glycine residues at CDRH2 ⁇ turn of the antibody; wherein if the antibody has one or more large cavities at the CDR regions, a significantly hydrophobic CDRH3 loop and contains one or more glycine residues at the ⁇ turn of CDRH2 loop, the antibody is identified or predicted as having low immunogenicity or likely to have low immunogenicity.
  • the method described herein further comprises using a model which is able to analyze one or more of the following features: cavity volume at the CDR regions of the antibody, hydrophobicity of CDRH3 loop of the antibody and information of the presence/absence of glycine residues at CDRH2 ⁇ turn of the antibody.
  • the sum of cavity volumes at the CDR regions is calculated by the FPOCKET program. In some embodiments, the sum of cavity volumes at CDR regions is about or more. In some embodiments, the sum of cavity volumes at CDR regions is about to For example, the sum of cavity volumes at CDR regions is about or a number or a range between any two of these values. In some embodiments, the sum of cavity volumes at CDR regions is about or more. In some embodiments, the sum of cavity volumes at CDR regions is about or more. In some embodiments, the sum of cavity volumes at CDR regions is about or more.
  • the hydrophobicity of CDRH3 loop is evaluated by exposed hydrophobic surface area.
  • the significantly hydrophobic CDRH3 loop has a ratio of hydrophobic surface to total surface for the CDRH3 loop of about 63%or more.
  • the significantly hydrophobic CDRH3 loop has a ratio of hydrophobic surface to total surface for the CDRH3 loop of about 63%to 80%.
  • the ratio of hydrophobic surface to total surface for the CDRH3 loop is about 63%, 64%, 65%, 67%, 68%, 69%, 70%, 74%, 80%, or a number or a range between any two of these values.
  • the ratio of hydrophobic surface to total surface for the CDRH3 loop is about 67%or more.
  • the CDRH3 hydrophobic surface area is about or a number or a range between any two of these values.
  • the ⁇ turn of CDRH2 loop (VH 52-56) has at least one glycine residue.
  • the ⁇ turn of CDRH2 loop (VH 52-56) has one glycine residue, two glycine residues, three glycine residues, or four glycine residues.
  • the ⁇ turn of CDRH2 loop (VH 52-56) has at least two glycine residues.
  • the model is called SVM model, which uses Support Vector Machine learning technology; features of antibodies with known immunogenicity are input into SVM model; parameters of SVM model are optimized in leave-one-out experiment; the trained SVM model is used for predicting immunogenicity.
  • the model analyzes two features: the cavity volume at the CDR regions and the hydrophobicity of CDRH3 loop. In some embodiments, the model analyzes two features: the hydrophobicity of CDRH3 loop and the information of the presence/absence of one or more glycine residues at CDRH2 ⁇ turn. In some embodiments, the model analyzes three features: the cavity volume at the CDR regions, the hydrophobicity of CDRH3 loop and the information of the presence/absence of one or more glycine residues at CDRH2 ⁇ turn.
  • the crystal structural of the antibody is available, which is used to calculate the cavity volume at the CDR regions and the hydrophobicity of CDRH3 loop.
  • the crystal structure of the antibody is unavailable, the ABodyBuilder program is used to predict the antibody structure, and then the cavity volume at the CDR regions and the hydrophobicity of CDRH3 loop are calculated.
  • a system for identifying or predicting antibody immunogenicity comprises a model described herein.
  • the system comprises:
  • an input device for inputting features of an antibody
  • an output device for outputting immunogenicity of the antibody.
  • the features of the antibody are calculated with the crystal structure of the antibody. In some embodiment, the features of the antibody are calculated with the predicted structure of the antibody. In some embodiment, the structure of the antibody is predicted by the ABodyBuilder program.
  • the system comprises:
  • an input device for inputting features of antibodies with known immunogenicity and a test antibody
  • At least one processor comprising a prediction module which predicts the structure of the test antibody and an analysis module which constructs a SVM model for analyzing immunogenicity using Support Vector Machine learning technology; wherein features described herein of antibodies with known immunogenicity are calculated and input into SVM model; parameters of SVM model are optimized in leave-one-out experiment; and the trained SVM model is used for identifying or predicting immunogenicity of the test antibody; and
  • an output device for outputting immunogenicity of the test antibody.
  • the analysis module analyzes two or more features selected from the list: cavity volume at the CDR regions of the antibody, hydrophobicity of CDRH3 loop of the antibody, or information of the presence/absence of glycine residues at CDRH2 ⁇ turn of the antibody; wherein if the antibody has two or more of one or more large cavities at the CDR regions, a significantly hydrophobic CDRH3 loop, or one or more glycine residues at the ⁇ turn of CDRH2 loop, the antibody is identified or predicted as having low immunogenicity or likely to have low immunogenicity.
  • the analysis module analyzes two features: cavity volume at the CDR regions of the antibody and hydrophobicity of CDRH3 loop of the antibody; wherein if the antibody has a one or more large cavity at the CDR regions and a significantly hydrophobic CDRH3 loop, the antibody is identified or predicted as having low immunogenicity or likely to have low immunogenicity.
  • the analysis module analyzes two features: hydrophobicity of CDRH3 loop of the antibody and information of the presence/absence of glycine residues at CDRH2 ⁇ turn of the antibody; wherein if the antibody has a significantly hydrophobic CDRH3 loop and contains one or more glycine residues at the ⁇ turn of CDRH2 loop, the antibody is identified or predicted as having low immunogenicity or likely to have low immunogenicity.
  • the analysis module analyzes three features: cavity volume at the CDR regions of the antibody, hydrophobicity of CDRH3 loop of the antibody and information of the presence/absence of glycine residues at CDRH2 ⁇ turn of the antibody; wherein if the antibody has one or more large cavities at the CDR regions, a significantly hydrophobic CDRH3 loop and contains one or more glycine residues at the ⁇ turn of CDRH2 loop, the antibody is identified or predicted as having low immunogenicity or likely to have low immunogenicity.
  • the cavity volume at the CDR regions is calculated by the FPOCKET program. In some embodiments, the sum of cavity volumes at the CDR regions is about or more. In some embodiments, the sum of cavity volumes at the CDR regions is about to about For example, the cavity volume at the CDR regions is about or a number or a range between any two of these values. In some embodiments, the sum of cavity volumes at the CDR regions is about or more. In some embodiments, the sum of cavity volumes at the CDR regions is about or more. In some embodiments, the sum of cavity volumes at the CDR regions is about or more.
  • the hydrophobicity of CDRH3 loop is evaluated by exposed hydrophobic surface area.
  • the ratio of hydrophobic surface to total surface for the CDRH3 loop is about 63%or more. In some embodiments, the ratio of hydrophobic surface to total surface for the CDRH3 loop is about 63%to about 80%.
  • the ratio of hydrophobic surface to total surface for the CDRH3 loop is about 63%, 64%, 65%, 67%, 68%, 69%, 70%, 74%, 80%, or a number or a range between any two of these values. In some embodiments, the ratio of hydrophobic surface to total surface for the CDRH3 loop is about 67%or more. In some embodiments, the CDRH3 hydrophobic surface area is about or a number or a range between any two of these values.
  • the ⁇ turn of CDRH2 loop (VH 52-56) has at least one glycine residue.
  • the ⁇ turn of CDRH2 loop (VH 52-56) has one glycine residue, two glycine residues, three glycine residues, or four glycine residues.
  • the ⁇ turn of CDRH2 loop (VH 52-56) has at least two glycine residues.
  • the crystal structural of the antibody is available, which is used to calculate the cavity volume at the CDR regions and the hydrophobicity of CDRH3 loop.
  • the crystal structure of the antibody is unavailable, the ABodyBuilder program is used to predict the antibody structure.
  • the cavity volume at the CDR regions and the hydrophobicity of CDRH3 loop are calculated with the modeled structure.
  • the analysis module analyzes two features: the cavity volume at the CDR regions and hydrophobicity of CDRH3 loop. In some embodiments, the analysis module analyzes two features: the hydrophobicity of CDRH3 loop and the information of the presence/absence of glycine residues at CDRH2 ⁇ turn. In some embodiments, the analysis module analyzes three features: the cavity volume at the CDR regions, the hydrophobicity of CDRH3 loop and the information of the presence/absence of glycine residues at CDRH2 ⁇ turn.
  • the algorithm developed in the present disclosure could provide extra benefit to select candidate antibodies with low immunogenicity for clinical trials, especially, when the crystal structures are available.
  • a humanized antibody which is predicted as low immunogenicity by computational tools, could be a better choice for clinical development than the full human antibody generated from the expensive platform of transgenic mice.
  • Figure 1 Distribution pattern of calculated humanness scores for CDR regions; Fig 1a, Humanized antibodies; Fig 1b, Full human antibodies.
  • Figure 2 Crystal structures of idiotype-anti-idiotype Fv complex.
  • the PDB code is shown for each complex structure.
  • FIG. 3 Comparison of backbone structures for immunogenic and non-immunogenic therapeutic antibodies.
  • Fig 3a 15 immunogenic antibodies;
  • Fig 3b 14 non-immunogenic antibodies.
  • the crystal structures of all the antibodies were obtained from PDB and superimposed to that of omalizumab (PDB code 4x7s) .
  • compositions and method are intended to mean that the compositions and method include the recited elements, but not excluding others. Embodiments defined by each of these transition features are within the scope of this disclosure.
  • CDRH2 is the second complementarity determining regions of the antibody heavy chains
  • CDRH3 is the third complementarity determining regions of the antibody heavy chains.
  • VH 52-56 are from amino acid residues from the 52th to 56th of the heavy chain variable regions. Kabat numbering scheme was used in this study as indicated in example.
  • Low immunogenicity (which includes non-immunogenicity) of antibodies means that treatment-emergent anti-antibody response (AAR) occurs (e.g., is reported) or is predicted to occur in less than 2%of patients. Otherwise, high immunogenicity of antibodies means that treatment-emergent anti-antibody response (AAR) occurs (e.g., is reported) or is predicted to occur in at least 2%of patients. Detectable AAR means that AAR is detected at least once during treatment if patients in studies are tested at multiple time points. “Likely to have low immunogenicity” or a similar phrase means that an antibody has a more than 50%chance of having low or no immunogenicity. In some embodiment, the antibody has an at least 60%, at least 65%, at least 70%or at least 75%chance of having low or no immunogenicity.
  • a pocket located at the CDR regions means that at least of two third of the surrounding atoms of the pocket are the CDR residues.
  • the hydrophobicity of CDRH3 is defined as the sum of solvent accessible surface of all hydrophobic atoms thereof.
  • the carbon, sulfur, and nitrogen atoms (excluding the non-protonated nitrogen atom of histidine side chain) are considered hydrophobic atoms.
  • a method for selecting a candidate therapeutic antibody with low immunogenicity comprises selecting an antibody having one or more large cavities at the CDR regions of the antibody, having a significantly hydrophobic surface area at the CDRH3 loop of the antibody, or containing one or more glycine residues at the ⁇ turn of CDRH2 loop of the antibody.
  • the candidate therapeutic antibody with low immunogenicity has one or more large cavities at the CDR regions, has a significantly hydrophobic CDRH3 loop, and contains one or more glycine residues at the ⁇ turn of CDRH2 loop.
  • the sum of cavity volumes at CDR regions is about or more. In some embodiments, the sum of cavity volumes at CDR regions is about to about In some embodiments, the significantly hydrophobic CDRH3 loop has a ratio of hydrophobic surface to total surface for the CDRH3 loop of about 63%or more. In some embodiments, the significantly hydrophobic CDRH3 loop has a ratio of hydrophobic surface to total surface for the CDRH3 loop of about 63%to about 80%. In some embodiments, the ⁇ turn of CDRH2 loop (VH 52-56) has at least one glycine residue.
  • the sum of cavity volumes at CDR regions is about or a number or a range between any two of these values.
  • the CDRH3 hydrophobic surface area is about or a number or a range between any two of these values.
  • the ⁇ turn of CDRH2 loop (VH 52-56) has one glycine residue, two glycine residues, three glycine residues, or four glycine residues.
  • the method comprises: increasing the cavity volume at the CDR regions of the antibody, increasing the hydrophobic surface area at the CDRH3 loop of the antibody, or introducing one or more glycine residues at the ⁇ turn of CDRH2 loop of the antibody.
  • the method comprises: increasing the cavity volume at the CDR regions of the antibody, increasing the hydrophobic surface area at the CDRH3 loop of the antibody, and introducing Gly at the ⁇ turn of CDRH2 loop of the antibody.
  • the sum of cavity volumes at CDR regions is increased to about or more. In some embodiments, the sum of cavity volumes at CDR regions is increased to about to about In some embodiments, the ratio of hydrophobic surface to total surface for the CDRH3 loop is increased to about 63%or more. In some embodiments, the ratio of hydrophobic surface to total surface for the CDRH3 loop is increased to about 63%to about 80%. In some embodiments, the ⁇ turn of CDRH2 loop (VH 52-56) has at least one glycine residue.
  • the sum of cavity volumes at CDR regions is increased to about or a number or a range between any two of these values.
  • the CDRH3 hydrophobic surface area is increased to about or a number or a range between any two of these values.
  • the ⁇ turn of CDRH2 loop (VH 52-56) has one glycine residue, two glycine residues, three glycine residues, or four glycine residues.
  • a method of producing an antibody with low immunogenicity comprises: increasing the cavity volume at the CDR regions of the antibody, increasing the hydrophobic surface area at the CDRH3 loop of the antibody, or adding one or more glycine residues at the ⁇ turn of CDRH2 loop of the antibody.
  • the antibody is antibody that has not been previously made.
  • the method of producing an antibody with low immunogenicity comprises designing an antibody having one or more large cavities at the CDR regions, a significantly hydrophobic surface area at the CDRH3 loop, and/or one or more glycine residues at the ⁇ turn of CDRH2 loop of the antibody, and producing the antibody.
  • designing the antibody can be done by the methods or systems described herein.
  • the antibody with low immunogenicity has one or more large cavities at the CDR regions, has a significantly hydrophobic CDRH3 loop, and contains one or more glycine residues at the ⁇ turn of CDRH2 loop.
  • the sum of cavity volumes at CDR regions is increased to about or more. In some embodiments, the sum of cavity volumes at CDR regions is increased to about to about In some embodiments, the significantly hydrophobic CDRH3 loop has a ratio of hydrophobic surface to total surface for the CDRH3 loop of about 63%or more. In some embodiments, the significantly hydrophobic CDRH3 loop has a ratio of hydrophobic surface to total surface for the CDRH3 loop of about 63%to about 80%. In some embodiments, the ⁇ turn of CDRH2 loop (VH 52-56) has at least one glycine residue.
  • the sum of cavity volumes at CDR regions is increased to about or a number or a range between any two of these values.
  • the CDRH3 hydrophobic surface area is increased to about or a number or a range between any two of these values.
  • the ⁇ turn of CDRH2 loop (VH 52-56) has one glycine residue, two glycine residues, three glycine residues, or four glycine residues.
  • an antibody produced by the method has one or more large cavities at the CDR regions, has a significantly hydrophobic CDRH3 loop, and contains one or more glycine residues at the ⁇ turn of CDRH2 loop. In some embodiments, the antibody is antibody that has not been previously made.
  • the sum of cavity volumes at CDR regions is about or more. In some embodiments, the sum of cavity volumes at CDR regions is about to about In some embodiments, the significantly hydrophobic CDRH3 loop has a ratio of hydrophobic surface to total surface for the CDRH3 loop of about 63%or more. In some embodiments, the significantly hydrophobic CDRH3 loop has a ratio of hydrophobic surface to total surface for the CDRH3 loop of about 63%to about 80%. In some embodiments, the ⁇ turn of CDRH2 loop (VH 52-56) has at least one glycine residue.
  • the sum of cavity volumes at CDR regions is about or a number or a range between any two of these values.
  • the CDRH3 hydrophobic surface area is about or a number or a range between any two of these values.
  • the ⁇ turn of CDRH2 loop (VH 52-56) has one glycine residue, two glycine residues, three glycine residues, or four glycine residues.
  • compositions comprising the antibody, optionally together with a suitable carrier, excipient or diluent.
  • the method comprises analyzing two or more features selected from the list: cavity volume at the CDR regions of the antibody, hydrophobicity of CDRH3 loop of the antibody, or information of the presence/absence of one or more glycine residues at CDRH2 ⁇ turn of the antibody; wherein if the antibody has two or more of one or more large cavities at the CDR regions, a significantly hydrophobic CDRH3 loop, or one or more glycine residues at the ⁇ turn of CDRH2 loop, the antibody is identified as having low immunogenicity or likely to have low immunogenicity.
  • the method comprises analyzing two or more features selected from the list: cavity volume at the CDR regions of the antibody, hydrophobicity of CDRH3 loop of the antibody, or information of the presence/absence of glycine residues at CDRH2 ⁇ turn of the antibody; wherein if the antibody has two or more of one or more large cavities at the CDR regions, a significantly hydrophobic CDRH3 loop, or one or more glycine residues at the ⁇ turn of CDRH2 loop, the antibody is predicted as having low immunogenicity or likely to have low immunogenicity.
  • the methods described herein further comprises using a model which is able to analyze one or more of the following features: cavity volume at the CDR regions of the antibody, hydrophobicity of CDRH3 loop of the antibody and information of the presence/absence of glycine residues at CDRH2 ⁇ turn of the antibody.
  • the crystal structural of the antibody is available, which is used to calculate the cavity volume at the CDR regions and the hydrophobicity of CDRH3 loop, and the method comprises constructing a model, which comprises two features: cavity volume at the CDR regions of the antibody and hydrophobicity of CDRH3 loop of the antibody; wherein if the antibody has one or more large cavities at the CDR regions and a significantly hydrophobic CDRH3 loop, the antibody is identified or predicted as having low immunogenicity or likely to have low immunogenicity.
  • the cavity volume at the CDR regions is calculated by the FPOCKET program and hydrophobicity of CDRH3 loop is evaluated by exposed hydrophobic surface area.
  • the crystal structure of the antibody is unavailable, and the ABodyBuilder program is used to predict the antibody structure.
  • the cavity volume at the CDR regions and the hydrophobicity of CDRH3 loop are calculated with the modeled structure.
  • the method comprises constructing a model, which analyzes two features: hydrophobicity of CDRH3 loop of the antibody and information of the presence/absence of one or more glycine residues at CDRH2 ⁇ turn of the antibody; wherein if the antibody has a significantly hydrophobic CDRH3 loop and contains one or more glycine residues at the ⁇ turn of CDRH2 loop, the antibody is identified or predicted as having low immunogenicity or likely to having low immunogenicity.
  • the hydrophobicity of CDRH3 loop is evaluated by exposed hydrophobic surface area.
  • the model is called SVM model, which uses Support Vector Machine learning technology; features of antibodies with known immunogenicity are input into SVM model; parameters of SVM model are optimized in leave-one-out experiment; the trained SVM model is used for identifying or predicting immunogenicity.
  • the sum of cavity volumes at CDR regions is about or more. In some embodiments, the sum of cavity volumes at CDR regions is about to about In some embodiments, the significantly hydrophobic CDRH3 loop has a ratio of hydrophobic surface to total surface for the CDRH3 loop of about 63%or more. In some embodiments, the significantly hydrophobic CDRH3 loop has a ratio of hydrophobic surface to total surface for the CDRH3 loop of about 63%to about 80%. In some embodiments, the ⁇ turn of CDRH2 loop (VH 52-56) has at least one glycine residue.
  • the sum of cavity volumes at CDR regions is about or a number or a range between any two of these values.
  • the CDRH3 hydrophobic surface area is about or a number or a range between any two of these values.
  • the ⁇ turn of CDRH2 loop (VH 52-56) has one glycine residue, two glycine residues, three glycine residues, or four glycine residues.
  • a system for identifying or predicting antibody immunogenicity comprising a model described herein.
  • the system comprises:
  • an input device for inputting features of antibodies with known immunogenicity and a test antibody
  • At least one processor comprising a prediction module which predicts the structure of the test antibody and an analysis module which constructs a SVM model for analyzing immunogenicity using Support Vector Machine learning technology; wherein features described herein of antibodies with known immunogenicity are calculated and input into SVM model; parameters of SVM model are optimized in leave-one-out experiment; the trained SVM model is used for identifying or predicting immunogenicity of the test antibody;
  • an output device for outputting immunogenicity of the test antibody.
  • the analysis module analyzes two or more features selected from the list: cavity volume at the CDR regions of the antibody, hydrophobicity of CDRH3 loop of the antibody, or information of the presence/absence of Gly at CDRH2 ⁇ turn of the antibody; wherein if the antibody has two or more of one or more large cavities at the CDR regions, a significantly hydrophobic CDRH3 loop, or one or more glycine residues at the ⁇ turn of CDRH2 loop, the antibody is identified or predicted as having low immunogenicity or likely to have low immunogenicity.
  • the crystal structural of the antibody is available, which is used to calculate the cavity volume at the CDR regions and the hydrophobicity of CDRH3 loop, and the analysis module analyzes two features: cavity volume at the CDR regions of the antibody and hydrophobicity of CDRH3 loop of the antibody; wherein if the antibody has one or more large cavities at the CDR regions and a significantly hydrophobic CDRH3 loop, the antibody is identified or predicted as having low immunogenicity or likely to have low immunogenicity.
  • the cavity volume at the CDR regions is calculated by the FPOCKET program and hydrophobicity of CDRH3 loop is evaluated by exposed hydrophobic surface area.
  • the crystal structure of the antibody is unavailable, the ABodyBuilder program is used to predict the antibody structure, and then hydrophobicity of the CDRH3 loop is calculated with the predicted structure of the antibody.
  • the analysis module analyzes two features: hydrophobicity of CDRH3 loop of the antibody and information of the presence/absence of one or more glycine residues at CDRH2 ⁇ turn of the antibody; wherein if the antibody has a significantly hydrophobic CDRH3 loop and contains one or more glycine residues at the ⁇ turn of CDRH2 loop, the antibody is identified or predicted as having low immunogenicity or likely to have low immunogenicity.
  • the hydrophobicity of CDRH3 loop is evaluated by exposed hydrophobic surface area.
  • the sum of cavity volumes at CDR regions is about or more. In some embodiments, the sum of cavity volumes at CDR regions is about to about In some embodiments, the significantly hydrophobic CDRH3 loop has a ratio of hydrophobic surface to total surface for the CDRH3 loop of about 63%or more. In some embodiments, the significantly hydrophobic CDRH3 loop has a ratio of hydrophobic surface to total surface for the CDRH3 loop of about 63%to 80%. In some embodiments, the ⁇ turn of CDRH2 loop (VH 52-56) has at least one glycine residue.
  • the sum of cavity volumes at CDR regions is about or a number or a range between any two of these values.
  • the CDRH3 hydrophobic surface area is about or a number or a range between any two of these values.
  • the ⁇ turn of CDRH2 loop (VH 52-56) has one glycine residue, two glycine residues, three glycine residues, or four glycine residues.
  • Antibodies designed or predicted by the methods or systems described herein can be produced by conventional methods.
  • the corresponding coding nucleic acid sequence can be designed by known methods, which can be introduced into host cells, such as CHO cells, HEK cells (e.g., HEK293F) , BHK cells, Cos1 cells, Cos7 cells, CV1 cells or mouse L cells, and the antibodies can be produced by culturing the cells in a suitable medium.
  • VH heavy chain
  • VL light chain
  • Crystal structures were available for 29 out of the 52 antibodies in the Protein Data Bank (PDB, https: //www. rcsb. org ) . Unless specifically indicated, statistical analysis of structural features for the 29 proteins (Table 3) was performed. Structural models for the other 23 antibodies (Table 4) were built with the online server ABodyBuilder to test the structure-based immunogenicity prediction algorithm developed in this study. Molecular graphics and analyses were performed with UCSF CHIMERA (Pettersen EF, et al., J Comput Chem, 2004, 25: 1605-12. ) for the protein structures.
  • the level of reported immunogenicity was obtained in the prescribing information for each therapeutic antibody at the FDA website ( https: //www. accessdata. fda. gov/scripts/cder/daf ) .
  • the observed immunogenicity of therapeutic proteins is highly dependent on several factors including assay methodology, underling disease, concomitant medications. If possible, data generated at the same conditions were used to separate immunogenic antibodies from non-immunogenic antibodies. For example, when the test results of multiple doses were available, the rate of antibody development was considered for patients receiving 10 mg/kg or similar dose.
  • Antibodies were classified as having low immunogenicity or non-immunogenic when treatment-emergent anti-antibody response (AAR) was reported in less than 2%of patients. Otherwise, the antibodies were considered having high immunogenicity or immunogenic. AAR was considered detectable if patients in studies were tested at multiple time points and the AAR was detected at least once during treatment. If AAR data with and without concomitant immunosuppression were concurrently reported, results from patients not taking immunosuppressants were used.
  • AAR treatment-emergent anti-antibody response
  • Residue humanness score is defined similarly to residue conservation score measured by the self-substitution score from the sequence profile as in the previous study. Sequence profiles were obtained by three rounds of PSI-BLAST searches against human sequences with the BLOSUM62 substitution matrix. The humanness score at position i is defined as
  • M ir is the self-substitution score in the position-specific substitution matrix generated from PSIBLAST for the residue type r at sequence position i
  • B rr is the diagonal element of BLOSUM62 for residue type r
  • r was defined as a rare residue in case S human is less than -6.
  • the sum of humanness scores was calculated for residues at the CDR regions and framework, respectively.
  • the FPOCKET program was used to identify all pockets in the Fv domain with default parameters and calculate the volume for each pocket.
  • the program was originally developed to identify cavities at the protein surface likely to bind small compounds. A pocket is considered to be located at the CDR region if two third of the surrounding atoms are of CDR residues. The sum of cavity volumes is calculated in case multiple pockets are identified at the CDR region.
  • the hydrophobicity of CDRH3 is defined as the sum of solvent accessible surface of all hydrophobic atoms thereof.
  • the carbon, sulfur, and nitrogen atoms (excluding the non-protonated nitrogen atom of histidine side chain) are considered hydrophobic atoms.
  • Hydrogen atoms, which were missing in the crystal structures, were added with the REDUCE program (Word JM, et al., J Mol Bio, 1999, 285: 1735-47) .
  • the solvent probe was set to The atomic radii of carbon, nitrogen, oxygen, sulfur, and polar hydrogen were set to 1.8, 1.65, 1.4, 1.85, and respectively, and non-polar hydrogen atoms were ignored.
  • the library for support vector machines LIBSVM-3.22 was downloaded from http: //www. csie. ntu. edu. tw/ ⁇ cjlin/libsvm and used for combining features and machine learning classification.
  • the optimal parameters for model training were derived by the recommended method through cross-validation.
  • the prediction accuracy is defined as the number of correctly predicted immunogenic and non-immunogenic antibodies divided by the number of total predictions.
  • the humanness score i.e., the distance to the human consensus sequence, was defined in a different way from other methods (Gao SH, et al., BMC Biotechnol, 2013, 13: 55; Clavero-Alvarez A et al., Sci Rep, 2018, 8: 14820. ) .
  • the humanness scores of full human antibodies are significantly higher than those of humanized antibodies at the CDR regions (p value ⁇ 10 -15 ) but the difference is minimal for the framework (Table 1) .
  • the humanness score was calculated as a negative number close to zero for human-like sequences and large in magnitude for non-human-like sequences.
  • T cell epitope is one of factors contributing to immune responses.
  • the activation of helper T cell is essential for B cell proliferation, antibody class switching, and an increase in antibody production.
  • Recognition of linear epitopes bound by MHC class II molecules on the surface of antigen presenting cells is a critical step for T cell activation.
  • the crystal structure of an idiotype-anti-idiotype complex precisely shows how the anti-idiotypic antibody binds the idiotypic antibody.
  • the study searched the PDB database with the key words “antibody” and “complex” and found 6 idiotype-anti-idiotype complexes from 1883 results in April 2018.
  • the anti-idiotypic antibody binds exclusively to the CDR regions of the idiotypic antibody, especially, the CDRH2 loop and the CDRH3 loop. Only a few atoms at the framework of the idiotypic antibody, i.e., B cell epitopes residing in the CDR regions, make direct contact with the anti-idiotypic antibody.
  • the study focused on the CDR regions in the following studies in order to identify features that distinguish immunogenic antibodies from non-immunogenic antibodies.
  • the study used the FPOCKET program (Le Guilloux V, et al., BMC bioinformatics, 2019, 10: 168. ) to identify the cavities at the CDR regions for an all-atom antibody structure and calculate the total cavity volume (Table 3) . Consistent with visual analysis, the cavity volume of immunogenic antibodies was found to be smaller than that of non-immunogenic antibodies The difference is statistically significant according to t student test (p value ⁇ 0.05) . Due to the large size of CDR regions, the study assumes that anti-idiotypic antibodies are not likely to bind the surface patch with a deep cavity, which is ideal for the binding of a small molecule on the other hand.
  • the CDRH3 loops of immunogenic antibodies have a significantly smaller hydrophobic surface area (p value ⁇ 0.05) than that of non-immunogenic antibodies (Table 3) . This is not caused by the slight difference of loop length. In fact, the ratio of hydrophobic surface to total surface is also smaller for the CDRH3 loops of the 15 immunogenic antibodies (62.5 ⁇ 10.2%) than that of the 14 non-immunogenic antibodies (67.4 ⁇ 4.3%) .
  • the study assumes that the antigen receptors, which potentially bind the therapeutic antibody with a hydrophobic CDRH3 loop, also bind similar self antibodies. As a result, the immature B cells with the cross-reactive antigen receptors on the surface are eliminated or inactivated during the early development and the foreign antibodies with a hydrophobic CDRH3 show low immunogenicity.
  • the CDRH2 loop is frequently located at the center of the binding site of an idiotypic antibody ( Figure 2) .
  • the ⁇ turn of CDRH2 loop (VH 52-56) is glycine rich for antibodies from various species for structural reasons but contains no glycine in 7 out of the 52 therapeutic antibodies.
  • 6 of the 7 antibodies are immunogenic.
  • the study infers that antibodies containing no glycine at the CDRH2 turn are immunogenic.
  • the study found the other humanized antibody, huBrE-3, with such an unusual CDRH2 loop.
  • the anti-drug antibodies were detectable in 1 out of 7 patient’s serum in the initial clinical evaluation (Kramer EL, et al., Clinical cancer research: an official journal of the American Association for Cancer Research 1998, 4: 1679-88. ) .
  • Support vector machine (SVM) learning technology was used to integrate the features discussed above for immunogenicity prediction.
  • the study achieved an impressive accuracy of 83%for the 29 therapeutic antibodies when the two features, cavity volume at the CDR regions and hydrophobicity of CDRH3 loop calculated from the crystal structures, were used in the leave-one-out experiment.
  • the accuracy was decreased to 76%by combining the information of presence/absence glycine at CDRH2 turn additionally due to over fit resulting from the small data set.
  • the SVM model trained with the two effective features of the 29 antibodies shows no predictive ability (48%accuracy) for the 23 test antibodies, of which the crystal structures are unavailable and the modeled structures have to be used for prediction.
  • the study found cavities at the CDR regions for all of 5 antibodies with an average volume of which makes them indistinguishable from non-immunogenic antibodies.
  • the exposed hydrophobic surface area of CDRH3 was fairly consistent with that of the observed structures for the 5 antibodies despite a small increase in most cases (339, 310, 245, 168, and versus 340, 176, 310, 112, and respectively) .
  • the study thus utilized another set of features, hydrophobicity of CDRH3 and the information of the presence/absence of glycine at CDRH2 turn, for SVM classification and achieved an accuracy of 79%in leave-one-out experiment for the 29 antibodies calculated with crystal structures.
  • the exposed hydrophobic surface area of CDRH3 of immunogenic antibodies was smaller than that of non-immunogenic antibodies for both crystal structures and modeled structures.
  • the surface area of CDRH3 could be systematically overestimated for the structures modeled by ABodyBuilder. Since the crystal structures usually were unavailable for the predicted antibodies, it was reasonable to use the modeled structures for SVM model training and prediction consistently.
  • hydrophobicity of CDRH3 loops calculated from the modeled structures and the information of the presence/absence of Gly at CDRH2 turn were used for SVM classification the study achieved an accuracy of 78%in leave-one-out experiment for the 23 test antibodies.
  • the prediction was made with modeled structures and the result was correct for 7 out of the 11 antibodies.

Abstract

L'invention concerne des procédés de sélection d'un anticorps thérapeutique candidat ayant une faible immunogénicité, des procédés de production d'un anticorps à faible immunogénicité, des procédés de réduction de l'immunogénicité d'un anticorps, des procédés d'identification de l'immunogénicité d'anticorps, des procédés de prédiction de l'immunogénicité d'anticorps, des systèmes d'identification ou de prédiction de l'immunogénicité d'anticorps, et des anticorps conçus ou produits à l'aide des procédés ou systèmes.
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WO2010054212A1 (fr) * 2008-11-06 2010-05-14 Alexion Pharmaceuticals, Inc. Mise au point d’anticorps à immunogénicité réduite et méthodes de fabrication associées
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WO2010054212A1 (fr) * 2008-11-06 2010-05-14 Alexion Pharmaceuticals, Inc. Mise au point d’anticorps à immunogénicité réduite et méthodes de fabrication associées
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