Monoclonal antibody therapy

Each antibody binds only one specific antigen.

Monoclonal antibody therapy is a form of immunotherapy that uses monoclonal antibodies (mAb) to bind monospecifically to certain cells or proteins. This may then stimulate the patient's immune system to attack those cells. Alternatively, in radioimmunotherapy a radioactive dose localizes on a target cell line, delivering lethal chemical doses.[1] More recently antibodies have been used to bind to molecules involved in T-cell regulation to remove inhibitory pathways that block T-cell responses, known as immune checkpoint therapy.[2]

It is possible to create a mAb specific to almost any extracellular/ cell surface target. Research and development is underway to create antibodies for diseases (such as rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, Ebola[3] and different types of cancers).

Antibody structure and function

Further information: Monoclonal antibodies

Immunoglobulin G (IgG) antibodies are large heterodimeric molecules, approximately 150 kDa and are composed of two kinds of polypeptide chain, called the heavy (~50kDa) and the light chain (~25kDa). The two types of light chains are kappa (κ) and lambda (λ). By cleavage with enzyme papain, the Fab (fragment-antigen binding) part can be separated from the Fc (fragment constant) part of the molecule. The Fab fragments contain the variable domains, which consist of three antibody hypervariable amino acid domains responsible for the antibody specificity embedded into constant regions. The four known IgG subclasses are involved in antibody-dependent cellular cytotoxicity.[4]

The immune system responds to the environmental factors it encounters on the basis of discrimination between "self" and "non-self". Tumor cells are generally not specifically targeted by the immune system, since tumor cells are the patient's own cells. Tumor cells, however are highly abnormal, and many display unusual antigens.

Some such tumor antigens are inappropriate for the cell type or its environment. Some normally present only during the organisms' development (e.g. fetal antigens).[4] Some are rare or absent in healthy cells, and are responsible for activating cellular signal transduction pathways that cause unregulated tumor growth. Examples include ErbB2, a constitutively active cell surface receptor that is produced at abnormally high levels on the surface of approximately 30% of breast cancer tumor cells. Such breast cancer is known as HER2-positive breast cancer.[5]

Antibodies are a key component of the adaptive immune response, playing a central role in both in the recognition of foreign antigens and the stimulation of an immune response to them. The advent of monoclonal antibody technology has made it possible to raise antibodies against specific antigens presented on the surfaces of tumors.[5]

History

Monoclonal antibodies for cancer. ADEPT: antibody directed enzyme prodrug therapy; ADCC: antibody-dependent cell-mediated cytotoxicity; CDC: complement-dependent cytotoxicity; MAb, monoclonal antibody; scFv, single-chain Fv fragment.[6]

Immunotherapy developed in the 1970s following the discovery of the structure of antibodies and the development of hybridoma technology, which provided the first reliable source of monoclonal antibodies.[7][8] These advances allowed for the specific targeting of tumors both in vitro and in vivo. Initial research on malignant neoplasms found mAb therapy of limited and generally short-lived success with blood malignancies.[9][10] Treatment also had to be tailored to each individual patient, which was impracticable in routine clinical settings.

Four major antibody types were developed: murine, chimeric, humanised and human. Antibodies of each type are distinguished by suffixes on their name.

Murine

Initial therapeutic antibodies were murine analogues (suffix -omab). These antibodies have: a short half-life in vivo (due to immune complex formation), limited penetration into tumour sites and inadequately recruit host effector functions.[11] Chimeric and humanized antibodies have generally replaced them in therapeutic antibody applications.[12] Understanding of proteomics has proven essential in identifying novel tumour targets.

Initially, murine antibodies were obtained by hybridoma technology, for which Jerne, Köhler and Milstein received a Nobel prize. However the dissimilarity between murine and human immune systems led to the clinical failure of these antibodies, except in some specific circumstances. Major problems associated with murine antibodies included reduced stimulation of cytotoxicity and the formation complexes after repeated administration, which resulted in mild allergic reactions and sometimes anaphylactic shock.[11] Hybridoma technology has been replaced by recombinant DNA technology, transgenic mice and phage display.[12]

Chimeric and humanized

To reduce murine antibody immunogenicity (attacks by the immune system against the antibody), murine molecules were engineered to remove immunogenic content and to increase immunologic efficiency.[11] This was initially achieved by the production of chimeric (suffix -ximab) and humanized antibodies (suffix -zumab). Chimeric antibodies are composed of murine variable regions fused onto human constant regions. Taking human gene sequences from the kappa light chain and the IgG1 heavy chain results in antibodies that are approximately 65% human. This reduces immunogenicity, and thus increases serum half-life.

Humanised antibodies are produced by grafting murine hypervariable regions on amino acid domains into human antibodies. This results in a molecule of approximately 95% human origin. Humanised antibodies bind antigen much more weakly than the parent murine monoclonal antibody, with reported decreases in affinity of up to several hundredfold.[13][14] Increases in antibody-antigen binding strength have been achieved by introducing mutations into the complementarity determining regions (CDR),[15] using techniques such as chain-shuffling, randomization of complementarity-determining regions and antibodies with mutations within the variable regions induced by error-prone PCR, E. coli mutator strains and site-specific mutagenesis.[1]

Human monoclonal antibodies

Human monoclonal antibodies (suffix -umab) are produced using transgenic mice or phage display libraries by transferring human immunoglobulin genes into the murine genome and vaccinating the transgenic mouse against the desired antigen, leading to the production of appropriate monoclonal antibodies.[12] Murine antibodies in vitro are thereby transformed into fully human antibodies.[5]

The heavy and light chains of human IgG proteins are expressed in structural polymorphic (allotypic) forms. Human IgG allotype is one of the many factors that can contribute to immunogenicity.[16][17]

Targeted conditions

Cancer

Anti-cancer monoclonal antibodies can be targeted against malignant cells by several mechanisms. Ramucirumab is a recombinant human monoclonal antibody and is used in the treatment of advanced malignancies.[18]

Autoimmune diseases

Monoclonal antibodies used for autoimmune diseases include infliximab and adalimumab, which are effective in rheumatoid arthritis, Crohn's disease and ulcerative Colitis by their ability to bind to and inhibit TNF-α.[19] Basiliximab and daclizumab inhibit IL-2 on activated T cells and thereby help preventing acute rejection of kidney transplants.[19] Omalizumab inhibits human immunoglobulin E (IgE) and is useful in moderate-to-severe allergic asthma.

Therapy types

Radioimmunotherapy

Radioimmunotherapy (RIT) involves the use of radioactively-conjugated murine antibodies against cellular antigens. Most research involves their application to lymphomas, as these are highly radio-sensitive malignancies. To limit radiation exposure, murine antibodies were chosen, as their high immunogenicity promotes rapid tumor clearance. Tositumomab is an example used for non-Hodgkins lymphoma.

Antibody-directed enzyme prodrug therapy

Antibody-directed enzyme prodrug therapy (ADEPT) involves the application of cancer-associated monoclonal antibodies that are linked to a drug-activating enzyme. Systemic administration of a non-toxic agent results in the antibody's conversion to a toxic drug, resulting in a cytotoxic effect that can be targeted at malignant cells. The clinical success of ADEPT treatments is limited.[20]

Antibody-drug conjugates

Antibody-drug conjugates (ADCs) are antibodies linked to one or more drug molecules. Typically when the ADC meets the target cell (eg a cancerous cell) the drug is released to kill it. Many ADCs are in clinical development. As of 2016 a few have been approved.

Immunoliposome therapy

Immunoliposomes are antibody-conjugated liposomes. Liposomes can carry drugs or therapeutic nucleotides and when conjugated with monoclonal antibodies, may be directed against malignant cells. Immunoliposomes have been successfully used in vivo to convey tumour-suppressing genes into tumours, using an antibody fragment against the human transferrin receptor. Tissue-specific gene delivery using immunoliposomes has been achieved in brain and breast cancer tissue.[21]

Checkpoint therapy

Checkpoint therapy uses antibodies and other techniques to circumvent the defenses that tumors use to suppress the immune system. Each defense is known as a checkpoint. Compound therapies combine antibodies to suppress multiple defensive layers. Known checkpoints include CTLA-4 targeted by ipilimumab, PD-1 targeted by nivolumab and pembrolizumab and the tumor microenvironment.[2]

The tumor microenvironment (TME) features prevents the recruitment of T cells to the tumor. Ways include chemokine CCL2 nitration, which traps T cells in the stroma. Tumor vasculature helps tumors preferentially recruit other immune cells over T cells, in part through endothelial cell (EC)–specific expression of FasL, ETBR, and B7H3. Myelomonocytic and tumor cells can up-regulate expression of PD-L1, partly driven by hypoxic conditions and cytokine production, such as IFNβ. Aberrant metabolite production in the TME, such as the pathway regulation by IDO, can affect T cell functions directly and indirectly via cells such as Treg cells. CD8 cells can be suppressed by B cells regulation of TAM phenotypes. Cancer-associated fibroblasts (CAFs) have multiple TME functions, in part through extracellular matrix (ECM)–mediated T cell trapping and CXCL12-regulated T cell exclusion.[22]

FDA approved therapeutic antibodies

For a more comprehensive list, see List of monoclonal antibodies.

The first FDA-approved therapeutic monoclonal antibody was a murine IgG2a CD3 specific transplant rejection drug, OKT3 (also called muromonab), in 1986. This drug found use in solid organ transplant recipients who became steroid resistant.[23] Hundreds of therapies are undergoing clinical trials. Most are concerned with immunological and oncological targets.

Example FDA approved therapeutic monoclonal antibodies[1]
AntibodyBrand name Company Approval date Type Target Indication
(Targeted disease)
abciximab ReoPro Eli Lilly 1994 chimericinhibition of glycoprotein IIb/IIIa Cardiovascular disease
adalimumab Humira Abbott Laboratories 2002 human inhibition of TNF-α signaling Several auto-immune disorders
alemtuzumab Campath Genzyme 2001 humanized CD52 Chronic lymphocytic leukemia
basiliximab Simulect Novartis 1998 chimeric IL-2Rα receptor (CD25) Transplant rejection
belimumab Benlysta GlaxoSmithKline 2011 human inihibition of B-cell activating factor Systemic lupus erythematosus
bevacizumab Avastin Genentech/Roche 2004 humanized Vascular endothelial growth factor (VEGF) Colorectal cancer, Age related macular degeneration (off-label), certain lung cancers, renal cancers, ovarian cancers, and glioblastoma multiforme of the brain
brentuximab vedotin Adcetris 2011 chimeric CD30 Anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma
canakinumab Ilaris Novartis 2009 human IL-1β Cryopyrin-associated periodic syndrome (CAPS)
cetuximab Erbitux Bristol-Myers Squibb/Eli Lilly/Merck KGaA 2004 chimeric epidermal growth factor receptor Colorectal cancer, Head and neck cancer
certolizumab pegol[24] Cimzia UCB (company) 2008 humanized inhibition of TNF-α signaling Crohn's disease
daclizumab Zenapax Genentech/Roche 1997 humanized IL-2Rα receptor (CD25) Transplant rejection
daratumumab Darzalex Genmab/Janssen Biotech 2015 human CD38 Multiple Myeloma
denosumab Prolia, Xgeva Amgen 2010 human RANK Ligand inhibitorPostmenopausal osteoporosis, Solid tumor`s bony metasteses
eculizumab Soliris Alexion Pharmaceuticals 2007 humanized Complement system protein C5 Paroxysmal nocturnal hemoglobinuria
efalizumab Raptiva Genentech/Merck Serono 2002 humanized CD11a Psoriasis
golimumab Simponi Johnson & Johnson/Merck & Co, Inc. 2009 human TNF-alpha inihibitor Rheumatoid arthritis, Psoriatic arthritis, and Ankylosing spondylitis
ibritumomab tiuxetan Zevalin Spectrum Pharmaceuticals, Inc. 2002 murine CD20 Non-Hodgkin lymphoma (with yttrium-90 or indium-111)
infliximabRemicade Janssen Biotech, Inc./Merck & Co 1998 chimeric inhibition of TNF-α signaling Several autoimmune disorders
ipilimumab (MDX-101) Yervoy Bristol-Myers Squibb 2011 human blocks CTLA-4 Melanoma
muromonab-CD3 Orthoclone OKT3 Janssen-Cilag 1986 murine T cell CD3 Receptor Transplant rejection
natalizumab Tysabri Biogen Idec/Élan 2006 humanized alpha-4 (α4) integrin, Multiple sclerosis and Crohn's disease
nivolumab Opdivo Bristol-Myers Squibb 2014 human blocks PD-1 Melanoma and SCC
ofatumumab Arzerra Genmab 2009 human CD20 Chronic lymphocytic leukemia
omalizumab Xolair Genentech/Novartis 2004 humanized immunoglobulin E (IgE) mainly allergy-related asthma
palivizumab Synagis MedImmune 1998 humanized an epitope of the RSV F protein Respiratory Syncytial Virus
panitumumab Vectibix Amgen 2006 human epidermal growth factor receptor Colorectal cancer
Pembrolizumab Keytruda Merck & Co 2014 humanized targets the programmed cell death 1 (PD-1) receptor melanoma and NSCLC
ranibizumab Lucentis Genentech/Novartis 2006 humanized Vascular endothelial growth factor A (VEGF-A) Macular degeneration
rituximab Rituxan, Mabthera Biogen Idec/Genentech 1997 chimeric CD20 Non-Hodgkin lymphoma
tocilizumab (or atlizumab) Actemra and RoActemra Hoffmann-La Roche 2010 humanised Anti- IL-6RRheumatoid arthritis
tositumomab Bexxar GlaxoSmithKline 2003 murine CD20 Non-Hodgkin lymphoma
trastuzumab Herceptin Genentech 1998 humanized ErbB2 Breast cancer
ustekinumab Stelara Centocor 2013 IL-12, IL-23 Psoriatic Arthritis, Plaque Psoriasis
vedolizumab Entyvio Takeda 2014 humanized integrin α4β7 Crohn's disease, ulcerative colitis

Recently, the bispecific antibodies, a novel class of therapeutic antibodies, have yielded promising results in clinical trials. In April 2009, the bispecific antibody catumaxomab was approved in the European Union.[25][26]

Economics

Since 2000, the therapeutic market for monoclonal antibodies has grown exponentially. The current “big 5” therapeutic antibodies on the market are bevacizumab, trastuzumab (both oncology), adalimumab, infliximab (both autoimmune and inflammatory disorders, ‘AIID’) and rituximab (oncology and AIID) accounted for 80% of revenues in 2006. In 2007, eight of the 20 best-selling biotechnology drugs in the U.S. are therapeutic monoclonal antibodies.[27] This rapid growth in demand for monoclonal antibody production has been well accommodated by the industrialization of mAb manufacturing.[28]

See also

References

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  2. 1 2 Sharma P, Allison JP (April 2015). "The future of immune checkpoint therapy". Science. 348 (6230): 56–61. Bibcode:2015Sci...348...56S. doi:10.1126/science.aaa8172. PMID 25838373.
  3. ↑ Olinger GG, Pettitt J, Kim D, Working C, Bohorov O, Bratcher B, Hiatt E, Hume SD, Johnson AK, Morton J, Pauly M, Whaley KJ, Lear CM, Biggins JE, Scully C, Hensley L, Zeitlin L (October 2012). "Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques". Proceedings of the National Academy of Sciences of the United States of America. 109 (44): 18030–5. Bibcode:2012PNAS..10918030O. doi:10.1073/pnas.1213709109. PMC 3497800Freely accessible. PMID 23071322.
  4. 1 2 Janeway, Charles; Paul Travers; Mark Walport; Mark Shlomchik (2001). Immunobiology; Fifth Edition. New York and London: Garland Science. ISBN 0-8153-4101-6.
  5. 1 2 3 Janeway CA, Jr.; et al. (2005). Immunobiology. (6th ed.). Garland Science. ISBN 0-443-07310-4.
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  7. ↑ Prof FC Breedveld (2000). "Therapeutic monoclonal antibodies". Lancet. 355 (9205): 735–740. doi:10.1016/S0140-6736(00)01034-5. PMID 10703815.
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  15. ↑ Chothia C, Lesk AM, Tramontano A, Levitt M, Smith-Gill SJ, Air G, Sheriff S, Padlan EA, Davies D, Tulip WR (1989). "Conformations of immunoglobulin hypervariable regions". Nature. 342 (6252): 877–83. Bibcode:1989Natur.342..877C. doi:10.1038/342877a0. PMID 2687698.
  16. ↑ Jefferis R, Lefranc MP (July–August 2009). "Human immunoglobulin allotypes: possible implications for immunogenicity". MAbs. 1 (4): 332–8. doi:10.4161/mabs.1.4.9122. PMC 2726606Freely accessible. PMID 20073133.
  17. ↑ Chapman K, Pullen N, Coney L, Dempster M, Andrews L, Bajramovic J, Baldrick P, Buckley L, Jacobs A, Hale G, Green C, Ragan I, Robinson V (2009). "Preclinical development of monoclonal antibodies: considerations for the use of non-human primates". MAbs. 1 (5): 505–16. doi:10.4161/mabs.1.5.9676. PMC 2759500Freely accessible. PMID 20065651.
  18. ↑ Vennepureddy A, Singh P, Rastogi R, Atallah JP, Terjanian T (June 2016). "Evolution of ramucirumab in the treatment of cancer - A review of literature". Journal of Oncology Pharmacy Practice. doi:10.1177/1078155216655474. PMID 27306885.
  19. 1 2 Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. p. 241. ISBN 0-443-07145-4.
  20. ↑ Francis RJ, Sharma SK, Springer C, Green AJ, Hope-Stone LD, Sena L, Martin J, Adamson KL, Robbins A, Gumbrell L, O'Malley D, Tsiompanou E, Shahbakhti H, Webley S, Hochhauser D, Hilson AJ, Blakey D, Begent RH (September 2002). "A phase I trial of antibody directed enzyme prodrug therapy (ADEPT) in patients with advanced colorectal carcinoma or other CEA producing tumours". British Journal of Cancer. 87 (6): 600–7. doi:10.1038/sj.bjc.6600517. PMC 2364249Freely accessible. PMID 12237768.
  21. ↑ Krauss WC, Park JW, Kirpotin DB, Hong K, Benz CC (2000). "Emerging antibody-based HER2 (ErbB-2/neu) therapeutics". Breast Disease. 11: 113–24. doi:10.3233/bd-1999-11110. PMID 15687597.
  22. ↑ Joyce JA, Fearon DT (April 2015). "T cell exclusion, immune privilege, and the tumor microenvironment". Science. 348 (6230): 74–80. Bibcode:2015Sci...348...74J. doi:10.1126/science.aaa6204. PMID 25838376.
  23. ↑ Hooks MA, Wade CS, Millikan WJ (1991). "Muromonab CD-3: a review of its pharmacology, pharmacokinetics, and clinical use in transplantation". Pharmacotherapy. 11 (1): 26–37. doi:10.1002/j.1875-9114.1991.tb03595.x (inactive 2016-07-10). PMID 1902291.
  24. ↑ Goel N, Stephens S (2010). "Certolizumab pegol". MAbs. 2 (2): 137–47. doi:10.4161/mabs.2.2.11271. PMC 2840232Freely accessible. PMID 20190560.
  25. ↑ Chames P, Baty D (2009). "Bispecific antibodies for cancer therapy: the light at the end of the tunnel?". MAbs. 1 (6): 539–47. doi:10.4161/mabs.1.6.10015. PMC 2791310Freely accessible. PMID 20073127.
  26. ↑ Linke, Rolf; Klein, Anke; Seimetz, Diane (2010). "Catumaxomab: Clinical development and future directions". MAbs. 2 (2): 129–136. doi:10.4161/mabs.2.2.11221. PMC 2840231Freely accessible. PMID 20190561.
  27. ↑ Scolnik PA (2009). "mAbs: a business perspective". MAbs. 1 (2): 179–84. doi:10.4161/mabs.1.2.7736. PMC 2725420Freely accessible. PMID 20061824.
  28. ↑ Kelley B (2009). "Industrialization of mAb production technology: the bioprocessing industry at a crossroads". MAbs. 1 (5): 443–52. doi:10.4161/mabs.1.5.9448. PMC 2759494Freely accessible. PMID 20065641.

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