Monoclonal antibody therapy

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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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

Cancer[edit]

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[edit]

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.

Alzheimer's disease[edit]

Humanised monoclonal antibodies targeting amyloid plaques in Alzheimer's disease include bapineuzumab, solanezumab and aducanumab. Many of the antibodies targeting amyloid-beta have the adverse effect of amyloid-related imaging abnormalities.[20]

Therapy types[edit]

Radioimmunotherapy[edit]

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[edit]

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.[21]

Antibody-drug conjugates[edit]

Antibody-drug conjugates (ADCs) are antibodies linked to one or more drug molecules. Typically when the ADC meets the target cell (e.g. 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[edit]

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.[22]

Checkpoint therapy[edit]

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[disambiguation needed], 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.[23]

FDA approved therapeutic antibodies[edit]

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.[24] Hundreds of therapies are undergoing clinical trials. Most are concerned with immunological and oncological targets.

FDA approved therapeutic monoclonal antibodies
Antibody Brand name Company Approval date Route Type Target Indication
(Targeted disease)
BLA STN Drug Label
abciximab ReoPro Centocor 12/22/1994 intravenous chimeric Fab GPIIb/IIIa Percutaneous coronary intervention 103575 Link
adalimumab Humira Abbvie 12/31/2002 subcutaneous fully human TNF Rheumatoid arthritis 125057 Link
adalimumab-atto Amjevita Amgen 9/23/2016 subcutaneous fully human, biosimilar TNF Rheumatoid arthritis
Juvenile idiopathic arthritis
Psoriatic arthritis
Ankylosing spondylitis
Crohn's disease
Ulcerative colitis
Plaque psoriasis
761024 Link
ado-trastuzumab emtansine Kadcyla Genentech 2/22/2013 intravenous humanized, antibody-drug conjugate HER2 Metastatic breast cancer 125427 Link
alemtuzumab Campath, Lemtrada Genzyme 5/7/2001 intravenous humanized CD52 B-cell chronic lymphocytic leukemia 103948 Link
alirocumab Praluent Sanofi Aventis 7/24/2015 subcutaneous fully human PCSK9 Heterozygous familial hypercholesterolemia
Refractory hypercholesterolemia
125559 Link
atezolizumab Tecentriq Genentech 5/18/2016 intravenous humanized PD-L1 Urothelial carcinoma 761034 Link
atezolizumab Tecentriq Genentech 10/18/2016 intravenous humanized PD-L1 Urothelial carcinoma
Metastatic non-small cell lung cancer
761041 Link
avelumab Bavencio EMD Serono 3/23/2017 intravenous fully human PD-L1 Metastatic Merkel cell carcinoma 761049 Link
basiliximab Simulect Novartis 5/12/1998 intravenous chimeric IL2RA Prophylaxis of acute organ rejection in renal transplant 103764 Link
belimumab Benlysta Human Genome Sciences 3/9/2011 intravenous fully human BLyS Systemic lupus erythematosus 125370 Link
bevacizumab Avastin Genentech 2/26/2004 intravenous humanized VEGF Metastatic colorectal cancer 125085 Link
bezlotoxumab Zinplava Merck 10/21/2016 intravenous fully human Clostridium difficile toxin B Prevent recurrence of Clostridium difficile infection 761046 Link
blinatumomab Blincyto Amgen 12/3/2014 intravenous mouse, bispecific CD19 Precursor B-cell acute lymphoblastic leukemia 125557 Link
brentuximab vedotin Adcentris Seattle Genetics 9/19/2011 intravenous chimeric, antibody-drug conjugate CD30 Hodgkin lymphoma
Anaplastic large-cell lymphoma
125388 Link
brodalumab Siliq Valeant 2/15/2017 subcutaneous chimeric IL17RA Plaque psoriasis 761032 Link
canakinumab Ilaris Novartis 6/17/2009 subcutaneous fully human IL1B Cryopyrin-associated periodic syndrome 125319 Link
capromab pendetide ProstaScint Cytogen 10/28/1996 intravenous murine, radiolabeled PSMA Diagnostic imaging agent in newly diagnosed prostate cancer or post-prostatectomy 103608 Link
certolizumab pegol Cimzia UCB (company) 4/22/2008 subcutaneous humanized TNF Crohn's disease 125160 Link
cetuximab Erbitux ImClone Systems 2/12/2004 intravenous chimeric EGFR Metastatic colorectal carcinoma 125084 Link
daclizumab Zenapax Roche 12/10/1997 intravenous humanized IL2RA Prophylaxis of acute organ rejection in renal transplant 103749 Link
daclizumab Zinbryta Biogen 5/27/2016 subcutaneous humanized IL2R Multiple sclerosis 761029 Link
daratumumab Darzalex Janssen Biotech 11/16/2015 intravenous fully human CD38 Multiple myeloma 761036 Link
denosumab Prolia, Xgeva Amgen 6/1/2010 subcutaneous fully human RANKL Postmenopausal women with osteoporosis 125320 Link
dinutuximab Unituxin United Therapeutics 3/10/2015 intravenous chimeric GD2 Pediatric high-risk neuroblastoma 125516 Link
dupilumab Dupixent Regeneron 3/28/2017 subcutaneous fully human IL4RA Atopic dermatitis 761055 Link
durvalumab Imfinzi AstraZeneca 5/1/2017 intravenous fully human PD-L1 Urothelial carcinoma 761069 Link
eculizumab Soliris Alexion 3/16/2007 intravenous humanized Complement component 5 Paroxysmal nocturnal hemoglobinuria 125166 Link
elotuzumab Empliciti Bristol-Myers Squibb 11/30/2015 intravenous humanized SLAMF7 Multiple myeloma 761035 Link
evolocumab Repatha Amgen 8/27/2015 subcutaneous fully human PCSK9 Heterozygous familial hypercholesterolemia
Refractory hypercholesterolemia
125522 Link
golimumab Simponi Centocor 4/24/2009 subcutaneous fully human TNF Rheumatoid arthritis
Psoriatic arthritis
Ankylosing spondylitis
125289 Link
golimumab Simponi Aria Janssen Biotech 7/18/2013 intravenous fully human TNF Rheumatoid arthritis 125433 Link
ibritumomab tiuxetan Zevalin Spectrum Pharmaceuticals 2/19/2002 intravenous murine, radioimmunotherapy CD20 Relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma 125019 Link
idarucizumab Praxbind Boehringer Ingelheim 10/16/2015 intravenous humanized Fab dabigatran Emergency reversal of anticoagulant dabigatran 761025 Link
infliximab Remicade Centocor 8/24/1998 intravenous chimeric TNF alpha Crohn's disease 103772 Link
infliximab-abda Renflexis Samsung Bioepis 4/21/2017 intravenous chimeric, biosimilar TNF Crohn's disease
Ulcerative colitis
Rheumatoid arthritis
Ankylosing spondylitis
Psoriatic arthritis
Plaque psoriasis
761054 Link
infliximab-dyyb Inflectra Celltrion Healthcare 4/5/2016 intravenous chimeric, biosimilar TNF Crohn's disease
Ulcerative colitis
Rheumatoid arthritis
Ankylosing spondylitis
Psoriatic arthritis
Plaque psoriasis
125544 Link
ipilimumab Yervoy Bristol-Myers Squibb 3/25/2011 intravenous fully human CTLA-4 Metastatic melanoma 125377 Link
ixekizumab Taltz Eli Lilly 3/22/2016 subcutaneous humanized IL17A Plaque psoriasis 125521 Link
mepolizumab Nucala GlaxoSmithKline 11/4/2015 subcutaneous humanized IL5 Severe asthma 125526 Link
natalizumab Tysabri Biogen Idec 11/23/2004 intravenous humanized alpha-4 integrin Multiple sclerosis 125104 Link
necitumumab Portrazza Eli Lilly 11/24/2015 intravenous fully human EGFR Metastatic squamous non-small cell lung carcinoma 125547 Link
nivolumab Opdivo Bristol-Myers Squibb 12/22/2014 intravenous fully human PD-1 Metastatic melanoma 125554 Link
nivolumab Opdivo Bristol-Myers Squibb 3/4/2015 intravenous fully human PD-1 Metastatic squamous non-small cell lung carcinoma 125527 Link
obiltoxaximab Anthem Elusys Therapeutics 3/18/2016 intravenous chimeric Protective antigen of the Anthrax toxin Inhalational anthrax 125509 Link
obinutuzumab Gazyva Genentech 11/1/2013 intravenous humanized CD20 Chronic lymphocytic leukemia 125486 Link
ocrelizumab Ocrevus Genentech 3/28/2017 intravenous humanized CD20 Multiple sclerosis 761053 Link
ofatumumab Arzerra Glaxo Grp 10/26/2009 intravenous fully human CD20 Chronic lymphocytic leukemia 125326 Link
olaratumab Lartruvo Eli Lilly 10/19/2016 intravenous fully human PDGFRA Soft tissue sarcoma 761038 Link
omalizumab Xolair Genentech 6/20/2003 intravenous humanized IgE Moderate to severe persistent asthma 103976 Link
palivizumab Synagis MedImmune 6/19/1998 intramuscular humanized F protein of RSV Respiratory syncytial virus 103770 Link
panitumumab Vectibix Amgen 9/27/2006 intravenous fully human EGFR Metastatic colorectal cancer 125147 Link
pembrolizumab Keytruda Merck 9/4/2014 intravenous humanized PD-1 Metastatic melanoma 125514 Link
pertuzumab Perjeta Genentech 6/8/2012 intravenous humanized HER2 Metastatic breast cancer 125409 Link
ramucirumab Cyramza Eli Lilly 4/21/2014 intravenous fully human VEGFR2 Gastric cancer 125477 Link
ranibizumab Lucentis Genentech 6/30/2006 intravitreal injection humanized VEGFR1
VEGFR2
Wet age-related macular degeneration 125156 Link
raxibacumab Raxibacumab Human Genome Sciences 12/24/2012 intravenous fully human Protective antigen of Bacillus anthracis Inhalational anthrax 125349 Link
reslizumab Cinqair Teva 3/23/2016 intravenous humanized IL5 Severe asthma 761033 Link
rituximab Rituxan Genentech 11/26/1997 intravenous chimeric CD20 B-cell non-Hodgkin's lymphoma 103705 Link
secukinumab Cosentyx Novartis 1/21/2015 subcutaneous fully human IL17A Plaque psoriasis 125504 Link
siltuximab Sylvant Janssen Biotech 4/23/2014 intravenous chimeric IL6 Multicentric Castleman's disease 125496 Link
tocilizumab Actemra Genentech 1/8/2010 intravenous humanized IL6R Rheumatoid arthritis 125276 Link
tocilizumab Actemra Genentech 10/21/2013 intravenous
subcutaneous
humanized IL6R Rheumatoid arthritis
Polyarticular juvenile idiopathic arthritis
Systemic juvenile idiopathic arthritis
125472 Link
trastuzumab Herceptin Genentech 9/25/1998 intravenous humanized HER2 Metastatic breast cancer 103792 Link
ustekinumab Stelara Centocor 9/25/2009 subcutaneous fully human IL12
IL23
Plaque psoriasis 125261 Link
ustekinumab Stelara Janssen Biotech 9/23/2016 subcutaneous
intravenous
fully human IL12
IL23
Plaque psoriasis
Psoriatic arthritis
Crohn's disease
761044 Link
vedolizumab Entyvio Takeda 5/20/2014 intravenous humanized integrin receptor Ulcerative colitis
Crohn's disease
125476 Link

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[edit]

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[edit]

References[edit]

  1. ^ a b Waldmann TA (March 2003). "Immunotherapy: past, present and future". Nature Medicine. 9 (3): 269–77. doi:10.1038/nm0303-269. PMID 12612576. 
  2. ^ a b 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. ^ a b Janeway, Charles; Paul Travers; Mark Walport; Mark Shlomchik (2001). Immunobiology; Fifth Edition. New York and London: Garland Science. ISBN 0-8153-4101-6. 
  5. ^ a b c Janeway CA, Jr.; et al. (2005). Immunobiology. (6th ed.). Garland Science. ISBN 0-443-07310-4. 
  6. ^ Modified from Carter P (November 2001). "Improving the efficacy of antibody-based cancer therapies". Nature Reviews. Cancer. 1 (2): 118–29. doi:10.1038/35101072. PMID 11905803. 
  7. ^ Prof FC Breedveld (2000). "Therapeutic monoclonal antibodies". Lancet. 355 (9205): 735–740. doi:10.1016/S0140-6736(00)01034-5. PMID 10703815. 
  8. ^ Köhler G, Milstein C (August 1975). "Continuous cultures of fused cells secreting antibody of predefined specificity". Nature. 256 (5517): 495–7. Bibcode:1975Natur.256..495K. doi:10.1038/256495a0. PMID 1172191. 
  9. ^ Nadler LM, Stashenko P, Hardy R, Kaplan WD, Button LN, Kufe DW, Antman KH, Schlossman SF (September 1980). "Serotherapy of a patient with a monoclonal antibody directed against a human lymphoma-associated antigen". Cancer Research. 40 (9): 3147–54. PMID 7427932. 
  10. ^ Ritz J, Schlossman SF (January 1982). "Utilization of monoclonal antibodies in the treatment of leukemia and lymphoma". Blood. 59 (1): 1–11. PMID 7032624. 
  11. ^ a b c Stern M, Herrmann R (April 2005). "Overview of monoclonal antibodies in cancer therapy: present and promise". Critical Reviews in Oncology/Hematology. 54 (1): 11–29. doi:10.1016/j.critrevonc.2004.10.011. PMID 15780905. 
  12. ^ a b c Hudson PJ, Souriau C (January 2003). "Engineered antibodies". Nature Medicine. 9 (1): 129–34. doi:10.1038/nm0103-129. PMID 12514726. 
  13. ^ Carter P, Presta L, Gorman CM, Ridgway JB, Henner D, Wong WL, Rowland AM, Kotts C, Carver ME, Shepard HM (May 1992). "Humanization of an anti-p185HER2 antibody for human cancer therapy". Proceedings of the National Academy of Sciences of the United States of America. 89 (10): 4285–9. Bibcode:1992PNAS...89.4285C. doi:10.1073/pnas.89.10.4285. PMC 49066Freely accessible. PMID 1350088. 
  14. ^ Presta LG, Lahr SJ, Shields RL, Porter JP, Gorman CM, Fendly BM, Jardieu PM (September 1993). "Humanization of an antibody directed against IgE". Journal of Immunology. 151 (5): 2623–32. PMID 8360482. 
  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. ^ a b Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. p. 241. ISBN 0-443-07145-4. 
  20. ^ Sperling, Reisa A.; Jack, Clifford R.; Black, Sandra E.; Frosch, Matthew P.; Greenberg, Steven M.; Hyman, Bradley T.; Scheltens, Philip; Carrillo, Maria C.; Thies, William (2011). "Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: Recommendations from the Alzheimer's Association Research Roundtable Workgroup". Alzheimer's & Dementia. 7 (4): 367–385. doi:10.1016/j.jalz.2011.05.2351. PMC 3693547Freely accessible. PMID 21784348. 
  21. ^ 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. 
  22. ^ 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. 
  23. ^ 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. 
  24. ^ 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 2017-01-21). PMID 1902291. 
  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. 

External links[edit]