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DRUG RECORD

 

MONOCLONAL ANTIBODIES

OVERVIEW
Monoclonal Antibodies

 

Monoclonal antibodies are antibodies that have a high degree of specificity (mono-specificity) for an antigen or epitope.  Monoclonal antibodies are typically derived from a clonal expansion of antibody producing malignant human plasma cells.  The initial monoclonal antibodies were created by fusing spleen cells from an immunized mouse with human or mouse myeloma cells (malignant self-perpetuating antibody producing cells), and selecting out and cloning the hybrid cells (hybridomas) that produced the desired antibody reactivity.  These initial monoclonal products were mouse antibodies and were very valuable in laboratory and animal research and diagnostic assays, but were problematic as therapeutic agents because of immune reactions to the foreign mouse protein.  Subsequently, production of chimeric mouse-human monoclonal antibodies and means of further “humanizing” them and producing fully human recombinant monoclonal antibodies were developed.  The conventions used in nomenclature of monoclonal antibodies indicate whether they are mouse (-omab), chimeric (-ximab), humanized (-zumab) or fully human (-umab).

Monoclonal antibodies have broad clinical and experimental medical uses.  Many of the initial monoclonal antibodies used in clinical medicine were immunomodulatory agents with activity against specific immune cells, such as CD4 or CD3 lymphocytes, which are important in the pathogenesis of rejection after solid organ transplantation.  Subsequently, monoclonal antibodies were prepared against specific cytokines (anti-cytokines), which were believed to play a role in cell and tissue damage in immunologically mediated diseases such as rheumatoid arthritis, alkylosing spondylitis, inflammatory bowel disease, multiple sclerosis and psoriasis, among others.  In addition, therapeutic monoclonal antibodies were developed, aimed at blocking or inhibiting the activity of specific enzymes, cell surface transporters or signaling molecules and have been used in cancer chemotherapy and to treat severe viral infections.  Use of monoclonal antibodies is currently broadening to therapy of other severe, nonmalignant conditions including asthma, atopic dermatitis, migraine headaches, hypercholesterolemia, osteoporosis and viral or bacterial infections.  Thus, the therapeutic monoclonal antibodies do not fall into a single class and have broad therapeutic uses.  As of 2018, more than 60 therapeutic monoclonal antibodies are approved and in use in the United States. 

Monoclonal antibodies are generally well tolerated.  Because they are large proteins (typically 150-200,000 daltons in size) they require parenteral, usually intravenous, administration.  Circulating proteins are metabolized by many cells, but particularly by hepatocytes.  Proteins undergo hepatic uptake by endocytosis and are either degraded or recycled to the cell surface for secretion.  The hepatic metabolism of antibodies often determines their half-life.  Proteins are broken down by cellular proteases into small peptides and amino acids that can used to synthesize other proteins.  Metabolism of proteins does not generate toxic intermediates and, therefore, monoclonal antibodies are unlikely to induce drug induced liver injury via production of toxic metabolites.  On the other hand, the peptides that are generated by the metabolism of the exogenously administered protein may ultimately be presented as foreign epitopes and generate an immune response.  In addition, the primary effect of the monoclonal antibody may generate a response, either immune or otherwise, that leads to an immune mediate hepatic injury.  Finally, monoclonal antibodies that suppress the immune system may cause reactivation of latent infections, including tuberculosis and hepatitis B.


Among the monoclonal antibodies that have been used in clinical medicine, only a few have been linked to drug induced liver injury and, in many situations, the cause of the hepatic adverse event is often unclear.  The monoclonal antibodies most clearly linked to drug-induced liver injury include the antibodies to tumor necrosis factor (anti-TNF such as infliximab, adalimumab, certolizumab and golimumab), to antibodies to check point proteins (anti-CTLA4 such as ipilimumab, anti-PD1 such as nivolumab and pembrolizumab and anti- PD-L1 such as atezolizumab, avelumab and durvalumab) and to antibodies to B cell markers and activation signals (anti-CD20 such as rituximab, ofatumumab and tositumomab).  The liver injury caused by these products is usually attributed to induction of autoimmunity or to immune modulation and reactivation of hepatitis B. 


Because of their fine specificity, monoclonal antibodies can also be used to direct more conventional therapeutic agents to specific organs, tissues or cells.  Several monoclonal antibody conjugates have been developed, largely in the therapy of cancer, the conjugated drug being an antineoplastic or cytotoxic agent.  Four such agents are gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab emtansine and inotuzumab ozogamicin.  These products combine a monoclonal antibody (anti-CD33, anti-CD30, anti-HER2, anti-CD22) to a microtubule inhibitor (ozogamicin, vedotin, emtansine).  These agents have been associated with serum enzyme elevations during therapy, and several have been linked to hepatic vascular damage, sinusoidal obstruction syndrome and nodular regenerative hyperplasia.  These forms of hepatotoxicity are likely due to the conjugate (the "payload") rather than the monoclonal antibody (the targeting vehicle).

Monoclonal antibodies available for clinical use in the United States are listed below with the type of monoclonal and specific antigen targeted in parentheses, followed by the year of approval and major use.  Those monoclonal antibodies with specific discussions of their hepatotoxicity in LiverTox are underlined and have a link to the corresponding record.



MONOCLONAL ANTIBODIES

Underlined Generic Names link to a LiverTox record.

CANCER
Generic Name
Brand Name
Type
Antigenic Target
Approval Likelihood
Score†
Major Uses
Alemtuzumab
Campath
Humanized
CD52
2001 E Chronic lymphocytic leukemia
Atezolizumab
Tecentriq
Humanized
PD-L1
2016 D Urothelial carcinoma
Non-small cell lung cancer
Avelumab
Bavencio
Human
PD-L1
2017 E* Merkel cell carcinoma
Urothelial carcinoma
Bevacizumab
Avastin
Humanized
VEGF

2004
2006

2009
2018

E

Colorectal cancer
Non-small cell lung cancer
Macular degeneration (off lbl) Renal cancer

Ovarian cancer

Blinatumomab
Blincyto
Mouse
CD3, CD19
2014 E Acute lymphoblastic leukemia
Brentuximab
Adcetris
Chimeric
CD30
2011 E Hodgkin lymphoma
Cetuximab
Erbitux
Chimeric
EGFR
2004 E Head and neck cancer
Colorectal cancer
Daratumumab
Darzalex
Human
CD38
2015 E Multiple myeloma
Dinutuximab
Unituxin
Chimeric
GD2
2015 E* Neuroblastoma
Durvalumab
Imfinzi
Human
PD-L1
2017 C Urothelial carcinoma
Elotuzumab
Empliciti
Humanized
SLAMF7
2015 D Multiple myeloma
Gemtuzumab
Mylotarg
Humanized
CD33
 2000
2017
A Acute myelogenous leukemia
Inotuzumab
Besponsa
Humanized
CD22
2017 B Acute lymphoblastic leukemia
Ipilimumab
Yervoy
Human
CTLA4
2011 A Malignant melanoma
Necitumumab
Portrazza
Human
EGFR
2015 E Non-small cell lung cancer
Nivolumab
Opdivo
Human
PD-1
2015
2018
E*

Malignant melanoma

Metastatic small cell lung cancer

Ofatumumab
Arzerra
Human
CD20
2009 E Chronic lymphocytic leukemia
Olaratumab
Lartruvo
Human
PDGF
2016 E* Soft tissue sarcoma
Panitumumab
Vectibix
Human
EGFR
2006 E* Colorectal cancer
Pembrolizumab
Keytruda
Humanized
PD-1
2014
2015
2018
E* Malignant melanoma
Non-small cell lung cancer
Advanced cervical cancer
Pertuzumab
Perjeta
Humanized
HER2
2012 E* Breast cancer
Ramucirumab
Cyramza
Human
VEGF
2014
2015
E* Gastric, non-small cell lung cancer
Colorectal cancer
Rituximab
Rituxan
Chimeric
CD20
1997 A Chronic lymphocytic leukemia
Non-Hodgkin lymphoma
Rheumatoid arthritis
Tositumomab
Bexxar
Mouse
CD20
2003 C Non-Hodgkin lymphoma
Trastuzumab
Herceptin
Humanized
HER2
1998 C Breast and gastric cancer
AUTOIMMUNE DISEASES
Generic Name
Brand Name
Type
Antigenic Target
Approval Likelihood
Score†
Major Uses
Adalimumab
Humira
Human
TNFα
2002 B Inflammatory bowel disease
Rheumatoid, psoriatic arthritis
Severe psoriasis
Belimumab
Benlysta
Human
B cell activity factor
2011 E Systemic lupus erythematosus
Brodalumab
Siliq
Human
IL-17A
2017 E Plaque psoriasis
Canakinumab
Ilaris
Human
IL1β
2009 E Autoinflammatory diseases
Certolizumab
Cimzia
Humanized
TNFα
2008 E* Inflammatory bowel disease
Rheumatoid arthritis
Daclizumab
Zinbryta
Humanized
CD25
2016 C Multiple sclerosis
Dupilumab
Dupixent
Human
IL-4α
2017 E Atopic dermatitis
Efalizumab
Raptiva
Humanized
CD11a
2003
Withdrawn
D Plaque psoriasis
Golimumab
Simponi
Human
TNFα
2009 E* Inflammatory bowel disease
Rheumatoid, psoriatic arthritis
Guselkumab
Tremfya
Human
IL-23
2017 E* Plaque psoriasis
Infliximab
Remicade
Chimeric
TNFα
1998 A Inflammatory bowel disease
Rheumatoid arthritis
Severe psoriasis
Ixekizumab
Taltz
Humanized
IL-17A
2016 E Plaque psoriasis
Psoriatic arthritis
Ocrelizumab
Ocrevus
Humanized
CD20
2017 E* Multiple sclerosis
Rituximab
Rituxan
Chimeric
CD20
1997 A Chronic lymphocytic leukemia
Non-Hodgkin lymphoma
Rheumatoid arthritis
Sarilumab
Kevzara
Human
IL6R
2017 E* Rheumatoid arthritis
Secukinumab
Cosentyx
Human
IL-17A
2015 E Plaque psoriasis
Psoriatic arthritis
Siltuximab
Sylvant
Chimeric
IL6
2014 E Castleman disease
Tildrakizumab
Ilumya
Humanized
IL-23
2018 E* Plaque psoriasis
Tocilizumab
Actemra
Humanized
IL6R
2010 D Rheumatoid arthritis
Ustekinumab
Stelara
Human
IL-12, IL-23
2010 E* Plaque psoriasis
Psoriatic arthritis
Vedolizumab
Entyvio
Humanized
Integrin α4β7
2014 E* Inflammatory bowel disease
LIVER TRANSPLANTATION
Generic Name
Brand Name
Type
Antigenic Target
Approval Likelihood
Score†
Major Uses
Basiliximab
Simulect
Chimeric
IL-2Rα
1998 E Prevention of transplant rejection
Daclizumab
Zenapax
Humanized
IL-2
1997
Withdrawn
E Prevention of transplant rejection
Muromonab-CD3
OKT3
Mouse
CD3 T cells
1986 E Prevention of transplant rejection
MISCELLANEOUS
Generic Name
Brand Name
Type
Antigenic Target
Approval Likelihood
Score†
Major Uses
Abciximab
Reopro
Chimeric
GpIIb/IIIa
1993   Inhibition of platelet aggregation
Alirocumab
Praluent
Human
PCSK9
2015 E Hypercholesterolemia
Benralizumab
Fasenra
Humanized
IL5
2017 E Asthma
Bezlotoxumab
Zinplava
Human
C. difficile toxin B
2016 E* Prevention of recurrence
of C. difficile infection
Burosumab
Crysvita
Human
FGF 23
2018 E X-linked Hypophosphatemia
Denosumab
Prolia, Zgeva
Human
RANKL
2010 E Osteoporosis
Bone metastases
Eculizumab
Soliris
Humanized
C5
2007
2011
D Paroxysmal nocturnal hemoglobinuria
Hypereosinophilic syndrome
Emicizumab
Hemlibra
Humanized
Factor IXa & X
2017 E Hemophilia A
Erenumab
Aimovig
Human
Calcitonin gene receptor
2018 E Migraine headache
Evolocumab
Repatha
Human
PCSK9
2015 E Hypercholesterolemia
Ibalizumab
Trogarzo
Humanized
CD4
2018 E HIV infection
Mepolizumab
Nucala
Humanized
IL15
2015 E Asthma
Hypereosinophilic syndrome
Natalizumab
Tysabri
Humanized
integrin α4β7
2004 C Multiple sclerosis
Inflammatory bowel disease
Obiltoxaximab
Anthim
Chimeric
Anthrax toxin
2016 E Inhalational anthrax
Omalizumab
Xolair
Humanized
IgE
2003 E Asthma
Palivizumab
Synagis
Humanized
RSV fusion protein
1998 E Respiratory syncytial virus infection
Ranibizumab
Lucentis
Humanized
VEGF-A
2006 E Macular degeneration
Raxibacumab Human
Anthrax toxin
2012 E Inhalational anthrax
Reslizumab
Cinqair
Humanized
IL5
2016 E Eosinophilic asthma

Likelihood Score indicates the likelihood of association with drug induced liver injury,

   based upon the known potential of the drug to cause such injury.

 

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