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Strategies and challenges for the next generation of therapeutic antibodies

Nature Reviews Immunology volume 10, pages 345352 (2010) | Download Citation

Abstract

Antibodies and related products are the fastest growing class of therapeutic agents. By analysing the regulatory approvals of IgG-based biotherapeutic agents in the past 10 years, we can gain insights into the successful strategies used by pharmaceutical companies so far to bring innovative drugs to the market. Many challenges will have to be faced in the next decade to bring more efficient and affordable antibody-based drugs to the clinic. Here, we discuss strategies to select the best therapeutic antigen targets, to optimize the structure of IgG antibodies and to design related or new structures with additional functions.

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References

  1. 1.

    What's fueling the biotech engine — 2008. Nature Biotechnol. 27, 987–993 (2009).

  2. 2.

    , & 5th European Antibody Congress 2009: November 30–December 2 2009. mAbs 2, 108–128 (2010).

  3. 3.

    , & Editorial: therapeutic antibodies and derivatives: from the bench to the clinic. Curr. Pharm. Biotechnol. 9, 421–422 (2008).

  4. 4.

    Antibodies to watch in 2010. mAbs 2, 1–16 (2010).

  5. 5.

    Fully human antibodies from transgenic mouse and phage display platforms. Curr. Opin. Immunol. 20, 450–459 (2008).

  6. 6.

    & Development trends for therapeutic antibody fragments. Nature Biotechnol. 27, 331–337 (2009).

  7. 7.

    Respiratory syncytial virus market. Nature Rev. Drug Discov. 9, 15–16 (2010).

  8. 8.

    Optimization of Fc-mediated effector functions of monoclonal antibodies. Curr. Opin. Biotechnol. 20, 685–691 (2009).

  9. 9.

    & Evolution of anti-CD20 monoclonal antibody therapeutics in oncology. mAbs 2, 1–6 (2010).

  10. 10.

    & Discovery and development of biopharmaceuticals: current issues. Curr. Opin. Biotechnol. 20, 668–672 (2009).

  11. 11.

    & FcγRIIB and the regulation of autoimmunity and infection: evolutionary and therapeutic implications. Nature Rev. Immunol. 10, 328–343 (2010).

  12. 12.

    & Therapeutic antibodies for autoimmunity and inflammation. Nature Rev. Immunol. 10, 301–316 (2010).

  13. 13.

    , & Monoclonal antibodies: versatile platforms for cancer immunotherapy. Nature Rev. Immunol. 10, 317–327 (2010).

  14. 14.

    & Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer. J. Clin. Oncol. 27, 5838–5847 (2009).

  15. 15.

    & More is less — combining targeted therapies in metastatic colorectal cancer. Nature Rev. Clin. Oncol. 6, 731–733 (2009).

  16. 16.

    & Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nature Rev. Cancer 9, 463–475 (2009).

  17. 17.

    & Integrins in cancer: biological implications and therapeutic opportunities. Nature Rev. Cancer 10, 9–22 (2010).

  18. 18.

    , , , & The IGF-I receptor in cell growth, transformation and apoptosis. Biochim. Biophys. Acta 1332, F105–F126 (1997).

  19. 19.

    & Insulin-like growth factor receptor type I as target for cancer therapy. Immunotherapy 1, 265–279 (2009).

  20. 20.

    , & Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nature Rev. Drug Discov. 7, 504–516 (2008).

  21. 21.

    & Antibody-based identification of cell surface antigens: targets for cancer therapy. Curr. Opin. Pharmacol. 8, 627–631 (2008).

  22. 22.

    et al. The RAV12 monoclonal antibody recognizes the N-linked glycotope RAAG12: expression in human normal and tumor tissues. Arch. Pathol. Lab. Med. 133, 1403–1412 (2009).

  23. 23.

    et al. Extending mass spectrometry contribution to therapeutic monoclonal antibody lead selection and development: characterization of antigen/antibody immune complexes using non-covalent ESI–MS. Anal. Chem. 81, 6364–6473 (2009).

  24. 24.

    & Tumor and stromal pathways mediating refractoriness/resistance to anti-angiogenic therapies. Trends Pharmacol. Sci. 30, 624–630 (2009).

  25. 25.

    et al. Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members. Oncogene 27, 3944–3956 (2008).

  26. 26.

    et al. The way forward, enhanced characterization of therapeutic antibody glycosylation: comparison of three level mass spectrometry-based strategies. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 872, 23–37 (2008).

  27. 27.

    et al. Identification and characterization of asparagine deamidation in the light chain CDR1 of a humanized IgG1 antibody. Anal. Biochem. 392, 145–154 (2009).

  28. 28.

    , , , & Determination of Fab-hinge disulfide connectivity in structural isoforms of a recombinant human immunoglobulin G2 antibody. Anal. Chem. 82, 1090–1099 (2010).

  29. 29.

    , & The effect of Fc glycan forms on human IgG2 antibody clearance in humans. Glycobiology 19, 240–249 (2009).

  30. 30.

    et al. Trends in glycosylation, glycoanalysis and glycoengineering of therapeutic antibodies and Fc-fusion proteins. Curr. Pharm. Biotechnol. 9, 482–501 (2008).

  31. 31.

    et al. Structural and functional characterization of disulfide isoforms of the human IgG2 subclass. J. Biol. Chem. 283, 16206–16215 (2008).

  32. 32.

    et al. Therapeutic IgG4 antibodies engage in Fab-arm exchange with endogenous human IgG4 in vivo. Nature Biotechnol. 27, 767–771 (2009).

  33. 33.

    et al. Specificity and affinity of human Fcγ receptors and their polymorphic variants for human IgG subclasses. Blood 113, 3716–3725 (2009).

  34. 34.

    Glycosylation as a strategy to improve antibody-based therapeutics. Nature Rev. Drug Discov. 8, 226–234 (2009).

  35. 35.

    et al. Engineered antibodies of IgG1/IgG3 mixed isotype with enhanced cytotoxic activities. Cancer Res. 68, 3863–3872 (2008).

  36. 36.

    et al. Antibody–drug conjugates for the treatment of non-Hodgkin's lymphoma: target and linker-drug selection. Cancer Res. 69, 2358–2364 (2009).

  37. 37.

    & Toward an effective targeted chemotherapy for multiple myeloma. Clin. Cancer Res. 15, 3906–3907 (2009).

  38. 38.

    et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nature Biotechnol. 26, 925–932 (2008).

  39. 39.

    et al. Therapeutic potential of an anti-CD79b antibody–drug conjugate, anti-CD79b–vc–MMAE, for the treatment of non-Hodgkin lymphoma. Blood 114, 2721–2729 (2009).

  40. 40.

    Antibody–drug conjugates ace the tolerability test. Nature Biotechnol. 26, 884–885 (2008).

  41. 41.

    , & Catumaxomab: clinical development and future directions. mAbs 2, 129–136 (2010).

  42. 42.

    & Bispecific antibodies for cancer therapy: the light at the end of the tunnel? mAbs 1, 539–547 (2009).

  43. 43.

    et al. Molecular construction and optimization of anti-human IL-1α/β dual variable domain immunoglobulin (DVD-Ig) molecules. mAbs 1, 339–347 (2009).

  44. 44.

    et al. Variants of the antibody herceptin that interact with HER2 and VEGF at the antigen binding site. Science 323, 1610–1614 (2009).

  45. 45.

    et al. Considerations for the development of therapeutic monoclonal antibodies. Curr. Opin. Immunol. 20, 493–499 (2008).

  46. 46.

    et al. Sym004: a novel synergistic anti-epidermal growth factor receptor antibody mixture with superior anticancer efficacy. Cancer Res. 70, 588–597 (2010).

  47. 47.

    , , & Manufacture of recombinant polyclonal antibodies. Biotechnol. Lett. 29, 845–852 (2007).

  48. 48.

    et al. Development of novel protein scaffolds as alternatives to whole antibodies for imaging and therapy: status on discovery research and clinical validation. Curr. Pharm. Biotechnol. 9, 502–509 (2008).

  49. 49.

    & Engineered protein scaffolds as next-generation antibody therapeutics. Curr. Opin. Chem. Biol. 13, 245–255 (2009).

  50. 50.

    2009 FDA drug approvals. Nature Rev. Drug Discov. 9, 89–92 (2010).

  51. 51.

    , & Fresh from the pipeline: ecallantide. Nature Rev. Drug Discov. 9, 189–190 (2010).

  52. 52.

    , & A European perspective on immunogenicity evaluation. Nature Biotechnol. 27, 507–508 (2009).

  53. 53.

    & How to systematically evaluate immunogenicity of therapeutic proteins — regulatory considerations. N. Biotechnol. 25, 280–286 (2009).

  54. 54.

    , & When binding is enough: nonactivating antibody formats. Curr. Opin. Immunol. 20, 479–485 (2008).

  55. 55.

    & New challenges to medicare beneficiary access to mAbs. mAbs 1, 56–66 (2009).

  56. 56.

    Industrialization of mAb production technology: the bioprocessing industry at a crossroads. mAbs 1, 443–452 (2009).

  57. 57.

    & Development and production of commercial therapeutic monoclonal antibodies in mammalian cell expression system: an overview of the current upstream technologies. Curr. Pharm. Biotechnol. 9, 447–467 (2008).

  58. 58.

    , & GlycoFi's technology to control the glycosylation of recombinant therapeutic proteins. Expert Opin. Drug Discov. 5, 95–111 (2010).

  59. 59.

    , & Economic issues with follow-on protein products. Nature Rev. Drug Discov. 7, 733–737 (2008).

  60. 60.

    & Toward biosimilar monoclonal antibodies. Nature Biotechnol. 26, 985–990 (2008).

  61. 61.

    , & European Medicines Agency workshop on biosimilar monoclonal antibodies: July 2, 2009, London, UK. mAbs 1, 394–416 (2009).

  62. 62.

    et al. Structural characterization of a human Fc fragment engineered for extended serum half-life. Mol. Immunol. 46, 1750–1755 (2009).

  63. 63.

    Gearing up for follow-on biologics. Nature Rev. Drug Discov. 8, 181 (2009).

  64. 64.

    et al. Genetic prognostic and predictive markers in colorectal cancer. Nature Rev. Cancer 9, 489–499 (2009).

  65. 65.

    et al. Biomarkers of response and resistance to antiangiogenic therapy. Nature Rev. Clin. Oncol. 6, 327–338 (2009).

  66. 66.

    & Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256, 495–497 (1975).

  67. 67.

    , , & Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains. Proc. Natl Acad. Sci. USA 81, 6851–6855 (1984).

  68. 68.

    , , , & Replacing the complementarity-determining regions in a human antibody with those from a mouse. Nature 321, 522–525 (1986).

  69. 69.

    , , & Phage antibodies: filamentous phage displaying antibody variable domains. Nature 348, 552–554 (1990).

  70. 70.

    et al. Antigen-specific human monoclonal antibodies from mice engineered with human Ig heavy and light chain YACs. Nature Genet. 7, 13–21 (1994).

  71. 71.

    et al. Antigen-specific human antibodies from mice comprising four distinct genetic modifications. Nature 368, 856–859 (1994).

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Affiliations

  1. Alain Beck, Thierry Wurch, Christian Bailly and Nathalie Corvaia are at the Centre d'Immunologie Pierre Fabre (CIPF), 5 Avenue Napoléon III, F74160, Saint-Julien-en-Genevois, France.

    • Alain Beck
    • , Thierry Wurch
    • , Christian Bailly
    •  & Nathalie Corvaia

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Competing interests

The authors are employees of the Pierre Fabre Research Institute, France, which has a collaboration agreement with Merck Research Laboratories for the development of insulin-like growth factor 1 receptor (IGF1R)-specific monoclonal antibodies dalotuzumab (MK-0646 or h7c10) and with Abbott for the development of hepatocyte growth factor receptor MET-specific antibodies.

Corresponding author

Correspondence to Alain Beck.

Glossary

Antibody-dependent cellular cytotoxicity

(ADCC). A mechanism of cell-mediated immunity whereby effector cells of the immune system (mainly natural killer cells) actively lyse a target cell that has been bound by specific antibodies. It is one of the mechanisms by which antibodies, as part of the humoral immune response, can limit and contain infection.

Biosimilar antibody

A generic version of an 'innovator' antibody with the same amino-acid sequence but produced from a different clone and manufacturing process, resulting in differences in glycosylation and other microvariations. Biosimilar antibodies are known as follow-on biologics in the United States.

Bispecific antibody

(Also known as a bifunctional antibody). A monoclonal antibody that binds to two different epitopes. These can be on the same antigen or two different antigens, thereby triggering two different functions. Bispecific antibodies do not usually occur naturally.

Chemistry, manufacture and control

(CMC). A part of pharmaceutical development that deals with the nature of the antibody drug substance and drug product, as well as the manner in which both are obtained, and by which the manufacturing process is quality controlled. Unfavourable physico-chemical characteristics of an antibody molecule that might result in difficulties to translate a research lead candidate into a scalable drug with appropriate pharmacokinetic and pharmacodynamic features are known as CMC liabilities (also referred to as 'drugability' or 'developability' issues).

Complement-dependent cytotoxicity

A mechanism of antibody-mediated immunity whereby antibody binding to the complement component C1q activates the classical complement activation cascade leading to formation of the membrane attack complex, the cytolytic end product of the complement cascade.

Complementarity-determining region

(CDR). A short sequence (up to 13 amino acids) found in the variable domains of immunoglobulins. The CDRs (six of which are present in IgG molecules) are the most variable part of immunoglobulins and contribute to their diversity by making contacts with a specific antigen, allowing immunoglobulins to recognize a vast repertoire of antigens with a high affinity.

Fab fragment

The fragment of antigen binding is the region of an antibody that binds to antigens. It is composed of one constant and one variable domain of each of the heavy and light chains (VH and VL, respectively).

Fc-fusion protein

An engineered recombinant protein carrying at its carboxy-terminal end the Fc portion (Hinge–CH2–CH3 domains) of an antibody and, at its amino-terminal end, any kind of protein or peptide such as a receptor-binding domain or a ligand. For example, etanercept, a product that is approved to treat rheumatoid arthritis by acting as a tumour necrosis factor inhibitor, is an Fc-fusion protein of IgG1 Fc with tumour necrosis factor receptor 2. The suffix -cept or -stim is used to identify Fc-fusion proteins or peptides, respectively.

Humanized antibody

A humanized antibody is obtained by genetic engineering to increase its similarity to antibodies produced naturally in humans, thereby decreasing its potential immunogenicity. A common humanization method is known as CDR grafting; this involves introducing the CDRs from a non-human antibody of interest into a framework acceptor sequence of a human germline V gene that is closely related to the antibody of interest. The suffix -zumab is used to identify humanized antibodies.

'Me better' antibody

(Also known as a 'bio-better' antibody). We define this as an antibody targeting the same validated epitope as an existing antibody (having the same CDRs: 'me too') but with an optimized glycosylation profile (such as low fucose levels for enhanced ADCC) or an engineered Fc domain to increase the serum half-life.

Microvariants

Antibodies with small structural differences (such as amino-terminal pyroglutamic acid residues, carboxy-terminal clipped lysine residues, different glycoforms or disulphide bridge isomers) that are present in the drug substance, which might affect the pharmacokinetic and pharmacodynamic properties and that must be kept in comparable amounts during the production scale-up (toxicology studies, Phases I, II and III clinical trials and post-marketing batches).

Orphan diseases

Rare diseases that affect only a small number of patients. Both the United States Food and Drug Administration and the European Medicines Agency have special development and regulatory procedures to stimulate research for such illnesses.

Paratope

The antigen-binding site of an antibody composed of portions of the different CDRs of the antibody's heavy and light chain variable domains.

PEGylation

The covalent attachment of polyethylene glycol polymer chains to a Fab fragment to increase the serum half-life.

Pharmacodynamics

The study of the physiological effects of the antibody, the mechanisms of drug action and the relationship between antibody concentration and effect: what an antibody does to a body.

Pharmacokinetics

The study of antibody clearance in the serum: what the body does to an antibody.

Protein scaffold

An engineered protein typically of small size (<100 amino acids) and containing a highly structured core associated with variable domains of high conformational tolerance, allowing insertions, deletions or other substitutions. These domains can create a putative binding interface for any targeted protein. The structure of protein scaffolds can be highly diverse (such as immunoglobulin-like molecules, loop-containing proteins, highly structured proteins and oligomeric proteins), but they are usually of human origin.

Second-generation antibody

A first-generation follow-up antibody with improved variable domains (such as humanized or human variable domains or affinity matured CDRs).

Third-generation antibody

A second-generation follow-up antibody with improved variable domains (such as humanized or human variable domains or affinity matured CDRs) and improved Fc domains (for example, glyco- or amino-acid engineered to increase effector functions or to improve half-life).

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DOI

https://doi.org/10.1038/nri2747

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