Skip Navigation

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.  Initial monoclonal antibodies 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, hypercholesterolemia, osteoporosis and viral or bacterial infections.  Thus, the therapeutic monoclonal antibodies do not fall into a single class and have broad therapeutic uses.

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.

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.  Two such agents are brentuximab vedotin and trastuzumab emtansine, both of which combine a monoclonal antibody (anti-CD30 and anti-HER2) to a microtubule inhibitor.  Both of these agents have been associated with serum enzyme elevations during therapy, and trastuzumab emastine possibly to hepatic vascular damage, sinusoidal obstruction syndrome and nodular regenerative hyperplasia.  These forms of hepatotoxicity are likely due to the conjugate rather than the monoclonal antibody.

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 unclear.  Monoclonal antibodies available for clinical use in the United States are listed below with the type of monoclonal and specific antigen targeted in parenthesis, 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*

Generic Name
Brand Name
Type
Antigenic Target
Approval Likelihood
Score†
Major Uses
Antineoplastic Agents
Rituximab
Rituxan
Chimeric
Anti-CD20
1997 A Chronic lymphocytic leukemia
Non-Hodgkin lymphoma
Rheumatoid arthritis
Trastuzumab
Herceptin
Humanized
Anti-HER2
1998 C Breast and gastric cancer
Gemtuzumab
Mylotarg
Humanized
Anti-CD33
2000
Withdrawn
A Acute myelogenous leukemia
Alemtuzumab
Campath
Humanized
Anti-CD52
2001 E Chronic lymphocytic leukemia
Tositumomab
Bexxar
Mouse
Anti-CD20
2003 C Non-Hodgkin lymphoma
Bevacizumab
Avastin
Humanized
Anti-VEGF
2004 E Colorectal cancer
Non-small cell lung cancer
Macular degeneration (off label)
Cetuximab
Erbitux
Chimeric
Anti-EGFR
2004 E Head and neck cancer
Colorectal cancer
Panitumumab
Vectibix
Human
Anti-EGFR
2006 E* Colorectal cancer
Ofatumumab
Arzerra
Human
Anti-CD20
2009 E Chronic lymphocytic leukemia
Brentuximab
Adcetris
Chimeric
Anti-CD30
2011 E Hodgkin lymphoma
Ipilimumab
Yervoy
Human
Anti-CTLA
2011 A Malignant melanoma
Pertuzumab
Perjeta
Humanized
Anti-HER2
2012 E* Breast cancer
Blinatumomab
Blincyto
Mouse
Anti-CD3, -CD19
2014 E Acute lymphoblastic leukemia
Pembrolizumab
Keytruda
Humanized
Anti-PD-1
2014
2015
E* Malignant melanoma
Non-small cell lung cancer
Ramucirumab
Cyramza
Human
Anti-VEGF
2014
2015
E* Gastric, non-small cell lung cancer
Colorectal cancer
Daratumumab
Darzalex
Human
Anti-CD38
2015 E Multiple myeloma
Dinutuximab
Unituxin
Chimeric
Anti-GD2
2015 E* Neuroblastoma
Elotuzumab
Empliciti
Humanized
Anti-SLAMF7
2015 D Multiple myeloma
Necitumumab
Portrazza
Human
Anti-EGFR
2015 E Non-small cell lung cancer
Nivolumab
Opdivo
Human
Anti-PD-1
2015 E* Malignant melanoma
Atezolizumab
Tecentriq
Humanized
Anti-PD-L1
2016 D Urothelial carcinoma
Non-small cell lung cancer
Olaratumab
Lartruvo
Human
Anti-PDGF
2016 E* Soft tissue sarcoma
Avelumab
Bavencio
Human
Anti-PD-L1
2017 E* Merkel cell carcinoma
Urothelial carcinoma
Durvalumab
Imfinzi
Human
Anti-PD-L1
2017
C Urothelial carcinoma
Inflammatory Bowel Disease/Rheumatoid Arthritis Agents
Rituximab
Rituxan
Chimeric
Anti-CD20
1997 A Chronic lymphocytic leukemia
Non-Hodgkin lymphoma
Rheumatoid arthritis
Infliximab
Remicade
Chimeric
Anti-TNFα
1998 A Inflammatory bowel disease
Rheumatoid arthritis
Severe psoriasis
Adalimumab
Humira
Human
Anti-TNFα
2002 B Inflammatory bowel disease
Rheumatoid, psoriatic arthritis
Severe psoriasis
Certolizumab
Cimzia
Humanized
Anti-TNFα
2008 E* Inflammatory bowel disease
Rheumatoid arthritis
Canakinumab
Ilaris
Human
Anti-IL1β
2009 E Autoinflammatory diseases
Golimumab
Simponi
Human
Anti-TNFα
2009 E* Inflammatory bowel disease
Rheumatoid, psoriatic arthritis
Tocilizumab
Actemra
Humanized
Anti-IL6R
2010 D Rheumatoid arthritis
Vedolizumab
Entyvio
Humanized
Anti-integrin α4β7
2014 E* Inflammatory bowel disease
Sarilumab
Kevzara
Human
Anti-IL6R
2017 E* Rheumatoid arthritis
Immunomodulatory/Immunosuppressive Agents
Efalizumab
Raptiva
Humanized
Anti-CD11a
2003
Withdrawn
D Plaque psoriasis
Ustekinumab
Stelara
Human
Anti-IL-12, -IL-23
2010 E* Plaque psoriasis
Psoriatic arthritis
Belimumab
Benlysta
Human
Anti-B cell activity factor
2011 E Systemic lupus erythematosus
Siltuximab
Sylvant
Chimeric
Anti-IL6
2014 E Castleman disease
Secukinumab
Cosentyx
Human
Anti-IL-17A
2015 E Plaque psoriasis
Psoriatic arthritis
Ixekizumab
Taltz
Humanized
Anti-IL-17A
2016 E Plaque psoriasis
Psoriatic arthritis
Brodalumab
Siliq
Human
Anti-IL-17A
2017 E Plaque psoriasis
Transplant Rejection Agents
Muromonab-CD3
OKT3
Mouse
Anti-CD3 T cells
1986 E Prevention of transplant rejection
Daclizumab
Zenapax
Humanized
Anti-IL-2
1997
Withdrawn
E Prevention of transplant rejection
Basiliximab
Simulect
Chimeric
Anti-IL-2Rα
1998 E Prevention of transplant rejection
Miscellaneous Agents
Abciximab
Reopro
Chimeric
Anti-GpIIb/IIIa
1993   Inhibition of platelet aggregation
Palivizumab
Synagis
Humanized
Anti-RSV fusion protein
1998 E Respiratory syncytial virus infection
Omalizumab
Xolair
Humanized
Anti-IgE
2003 E Asthma
Mepolizumab
Nucala
Humanized
Anti-IL15
2015 E Asthma
Hypereosinophilic syndrome
Natalizumab
Tysabri
Humanized
Anti-integrin α4β7
2004 C Multiple sclerosis
Inflammatory bowel disease
Ranibizumab
Lucentis
Humanized
Anti-VEGF-A
2006 E Macular degeneration
Eculizumab
Soliris
Humanized
Anti-C5
2007
2011
D Paroxysmal nocturnal hemoglobinuria
Hypereosinophilic syndrome
Denosumab
Prolia, Zgeva
Human
Anti-RANKL
2010 E Osteoporosis
Bone metastases
Raxibacumab Human
Anti-anthrax toxin
2012 E Inhalational anthrax
Alirocumab
Praluent
Human
Anti-PCSK9
2015 E Hypercholesterolemia
Evolocumab
Repatha
Human
Anti-PCSK9
2015 E Hypercholesterolemia
Bezlotoxumab
Zinplava
Human
Anti-C. difficile toxin B
2016 E* Prevention of recurrence
of C. difficile infection
Obiltoxaximab
Anthim
Chimeric
Anti-anthrax toxin
2016 E Inhalational anthrax
Reslizumab
Cinqair
Humanized
Anti-IL5
2016 E Eosinophilic asthma

* Underlined Name indicates the availability of a LiverTox record.

Likelihood Score indicates the likelihood of association with drug induced

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

 

Top of page