Targets and approvals for monoclonal antibodies and derivatives (asterisks denote approvals in USA only)
| Target | Function | FDA-approved mAbs, Traps, Bi-specific mAbsB | Autoimmune | Malignancy | Cardiovascular | Other/comments |
|---|---|---|---|---|---|---|
| CD52 | Marker of T- and B-lymphocyte subsets | Alemtuzumab (Lemtrada) | Multiple sclerosis | Chronic lymphocytic leukemia | Trade name changed from Campath-1H (cancer) to Lemtrada (multiple sclerosis) Humanised IgG1k | |
| CD41 (glycoprotein llb/IIIa) | Platelet aggregation inhibitor | Abciximab (ReoPro) | Perisurgical anti-thrombosis | Mouse/human IgG1 | ||
| Fab fragment | ||||||
| CD25 | Alpha-chain of the IL-2 receptor | Basiliximab (Simulect) | Multiple sclerosis | Basiliximab: chimeric mouse/human IgG1k. | ||
| Daclizumab (Zenapax) | Transplant rejection | Daclizumab: humanised IgG1k. | ||||
| CD19/CD3 | Bi-specific T-cell directed killing of CD19 | Blinatumomab (Blincyto) | B-cell precursor acute lymphoblastic leukemia | |||
| CD20 | Participates in B-cell differentiation | Obinutuzumab (Gazyva)Ibritumomab tiuxetan (Zevalin) | Rheumatoid arthritis | B-cell malignancies | Obintuzumab is the first approved glycoengineered IgG1 mAb with enhanced ADCC. | |
| Tositumumab (Bexxar)* Ofatumumab (Arzerra) Rituximab (Rituxan) | Rituximab is chimeric mouse/human IgG1k Ibritumomab tiuxetan and tositumumab are radio-conjugates that can be used when tumours stop responding to the anti-CD20 mAbs. | |||||
| Ibritumumab and tositumumab are mouse IgG2a. | ||||||
| CD30 | Member of the TNF receptor family | Brentuximab vedotin (Adcetris) | Hodgkin lymphoma, anaplastic large cell lymphoma | Second approved antibody-drug conjugate | ||
| CD38 | Cyclic ADP ribose synthetase leads to generation of adenosine in the tumour microenvironment (immunosuppression); co-stimulatory receptor; more? | Daratumumab (Darzalex) | Multiple myeloma | |||
| CD80/CD86 | Provide co-stimulatory signals necessary for T-cell activation and survival. Ligand trap prevents activation of CD28 immune checkpoint resulting in immune suppression | Nolojix Orencia (both CTLA4-Fc fusion proteins) | Rheumatoid arthritis Transplant rejection | |||
| CD279/PD-1 | Immune ‘checkpoint’ receptor that suppresses immune response after binding to PDL-1 or 2 | Nivolumab (Opdivo) Pembrolizumab (Keytruda) | Melanoma, non-small cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck squamous carcinoma | These mAbs designed not to be immune active (eg no ADCC): IgG4. This allows the mAbs to increase activity of T-cells without inducing apoptosis PDL-1 is a biomarker for pembrolizumab | ||
| CD274/PDL-1 | Tumour-expressed protein that activates the PD-1 immune suppression pathway | Atezolizumab (Tecentriq) Avelumab (Bavencio)* | Urothelial (bladder) carcinoma, non-small cell lung cancer merkel cell carcinoma | Atezolizumab: IgG1k mAb engineered to lack ADCC activity PDL-1 is biomarker (Avelumab: intact IgG1k)** Active IgG1 targets tumour cells. Approval likely | ||
| CTLA4/CD152 | When activated through binding CD80/86 this receptor turns down cytotoxic T-cells | Ipilimumb (Yervoy) | Metastatic melanoma, mesothelioma | This is the first of the immuno-oncology mAbs to be approved (IgG1k). Largely due to efforts of J Allison (ref PMID 16730267) | ||
| Glycolipid GD2 | Disialoganglioside preferentially expressed on tumours of neuroectodermal origin | Dinutuximab (Unituxin) | Neuroblastoma | Mouse/human chimeric IgG1k. Induces severe pain managed by morphine | ||
| HER2 | A growth factor-like receptor tyrosine kinase without a known ligand | Trastuzumab (Herceptin) Pertuzumab (Perjeta) Ado-trastuzumab emtansine (Kadcyla) | Breast, gastric adenocarcinoma | Two monoclonal antibodies (T,P) and one ADC (ado-trastuzumab) Overexpression of HER2 leads to spontaneous signaling Crosslinking with mAb leads to internalization First commercially successful ADC (Lewis et al, PMID 19010901)Biomarker driven therapy | ||
| EGFR (receptor for multiple growth factors) | Many tumours are addicted to the EGFR signalling pathway | Cetuximab (Erbitux) Panitumumab (Vectibix) | Squamous cell carcinoma of the head and neck, colorectal cancer, non-small cell lung cancer | Biomarker: usually requires EGFR IHC positivity; always requires test for normal ras oncogene Cetuximab is mouse/human chimeric IgG1; Vectibix is human IgG2 from recombinant mice | ||
| TNF-alpha | Inflammatory cytokine that drives multiple autoimmune diseases* | Adalimumab (Humira) Certolizumab pegol (Cimzia) Golimumab (Simponi) Infliximab (Remicade) Etanercept (Enbrel) There are more than 20 anti-TNF biosimilars in various stages of development. Already approved are infliximab biosimilars (Remsina, Inflectra, Flexiabi), etanercept biosimilars (Erelzi, Benepali), adalimumab biosimilars (Amjevita). This field will change very rapidly as many dossiers are now under regulatory scrutiny. Biosimilars are given a suffix, eg etanercept-szzs (Erlezi) | Crohn's disease, ulcerative colitis, RA, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, hidradentis suppurtiva, uveitis | Not all TNF blockers are approved for all indications Drugs in italics are biosimilars: adalimumab, infliximab, infliximab, inflectra, adalimumab-atto are IgG1k mAbs; certolizumab pegol is a pegylated Fab fragment; etanercept is a soluble Fc: TNF receptor ‘trap’ that binds TNF (there is one biosimilar) At least four biosimilar TNF-blockers have been approved in the EU (two each for infliximab and etanercept) | ||
| VEGF | Cytokine that stimulatesvasculogenesis and angiogenesis. Overproduced in some inflammatory disorders and tumours to induce increased blood supply. | Bevacizumab (Avastin) Ramucirumab (Cyramza)Aflibercept (Eylea/Zaltrap) Ranibizumab (Lucentis) | Age-related macular degeneration, macular oedema, diabetic macular oedema, diabetic retinopathy | Colorectal cancer, Non-squamous NSCLC, breast cancer, glioblastoma, renal cell carcinoma, gastric cancer or gastro-esophageal junction adenocarcinoma | Bevacizumab, ramucirumab are IgG1 mAbs for cancer therapy (ramucirumab was derived from phage display); ranibizumab is a Fab fragment (single arm binder). It has a short half-life if administered intravenously, but it is stable and effective when locally injected into the eye Aflibercept is a ligand trap with optical (Eylea) and cancer (Zaltrap) applications | |
| IgE | Binds to mast cells, basophils, other cells that express Fc-epsilon receptor, and induces release of inflammatory cytokines | Omalizumab (Xolair) | Asthma | IgG1k mAb also used off-label to treat IgE-related conditions (allergic rhinitis, drug allergies, other) | ||
| Alpha-4 integrin | Alpha-4 integrin facilitates exit of inflammatory cells from blood into intestine or across the blood brain barrier | Vedolizumab (Entyvio) Natalizumab (Tysabri) | Multiple sclerosis, Crohn's disease and ulcerative colitis | IgG4 natalizumab therapy has been associated with PML caused by John Cunningham virus in immunocompromised patients. IgG1k vedolizumab MAY not be associated with PML. | ||
| Complement C5 | Inhibits complement cascade | Eculizumab (Solaris) | Prevents destruction of red blood cells by activated complement (paroxysmal nocturnal hemoglobinuria) | IgG2/4 mAbMost expensive drug in the world ($409,500 annually) | ||
| Interleukin-1 | Mutations in cryopyrin lead to overproduction of IL-1 and inflammatory disease; IL-1 also drives other inflammatory diseases | Canakinumab (Ilaris)Rilonacept (Arcalyst)* | Rare inflammatory syndromes, active juvenile arthritis, gouty arthritis | Canakinumab is an IgG1k mAb; rilonacept is an IL-1 ‘trap’ designed from the IL-1R fused with human mAb Fc region. | ||
| P40 subunit of IL-12 and IL-23 | Prevents cytokine (inflammatory) activation of cellular receptors | Ustekinumab (Stelara) | Plaque and psoriatic arthritis, Crohn's disease | IgG1k human mAb from recombinant mice | ||
| Receptor activator of NF kappa-B ligand (RANKL) | Activates osteoclastic bone resorption | Denosumab (Xgeva) | Can be used to prevent bone mass loss in cancer patients | Human IgG2 mAb inhibits bone resorption and enhances bone mass (due to multiple causes) | ||
| Interleukin-6 | Overexpression of IL-6 is associated with multiple malignancies | Siltuximab (Sylvant) | Pseudo-malignancy: Castleman's disease (similar to lymphoma) | Murine/human chimeric IgG1κ | ||
| IL-6R (Interleukin 6 receptor) | Current approvals based upon role of IL-6 in promoting inflammatory autoimmune disease | Tocilizumab (Actemra) | Rheumatoid arthritis, polyarticular juvenile arthritis, juvenile idiopathic arthritis | Human/mouse chimeric mAb with initial approval for efficacy vs RA after failure of TNF blocker | ||
| BAFF (tumour necrosis factor superfamily member 13b) | Role in proliferation and differentiation of B-cells | Belimumab (Benlysta) | Systemic lupus erythematosus | IgG1-gamma/lambda | ||
| Bacillus anthraces (anthrax) toxin | Recognises the protective antigen portion of the toxin produced by Bacillus anthracis and prevents the toxin from entering cells and killing them | Obiltoxaximab (Anthim)* | Chimeric human/mouse chimeric mAb to anthrax toxin for prevention and treatment | |||
| PCSK9 | PCSK9 binds to LDLR, causing it to be degraded. With the result of higher blood levels of LDL mAb vs PCSK9 prevents degradation of LDLR and thereby increases LDL removal from blood. Therefore, blocking PCSK9 can lower blood cholesterol levels | Evolocumab (Repatha) Alirocumab (Praluent) | Second line treatment for high cholesterol for adults whose cholesterol is not controlled by diet and statin treatment. Perhaps most important for hereditary high cholesterol | Evolocumab: IgG2 for low ADCC Alirocumab is IgG1k | ||
| SLAMF7/CD319 | SLAM7 triggers the activation and differentiation of a wide variety of immune cells (innate and adaptive immune response) perhaps primarily mediated by natural killer cells and myeloma cells | Elotuzumab (Empliciti) | Multiple myeloma | This IgG1k mAb is thought to activate SLAM7 receptor and to have a secondary mechanism of mediating ADCC vs multiple myeloma cells | ||
| Dabigatran | Anti-coagulant | Idarucizumab (Praxbind) | This Fab fragment sequesters dabigatran and clears it from blood, reversing anti-coagulation | |||
| IL-5 | Induces differentiation and survival of eosinophils | Reslizumab (Cinqair) Mepolizumab (Nucala) | Asthma | Both IgG1k mAbs | ||
| IL-17A | Inflammatory cytokine | Ixekizumab (Taltz) Secukinumab (Cosentyx) | Plaque psoriasis, ankylosing spondylitis | Ixekizumab is an IgG4; secukinumab is an IgG1k | ||
| Clostridium | Reduce recurrence of Clostridium difficile recurrence | Bezlotoxumab (Zinplava) Actoxumab | Meant to be used for the prevention of recurring clostridial disease. Actoxumab is only approved in the UK. | |||
| PDGF | Inhibit association of the PDGF with its receptor | Olaratumab (Lartruvo) | Soft tissue sarcoma | Human IgG1k that prevents interaction of PDGF with its receptor(s) |
An actively updated summary of MAb approvals can be found at www.antibodysociety.org.
MMabs can be murine, chimeric (human Fc region), humanised or human; Ttraps are derived from receptors and compete with natural receptor for binding target; Bbi-specific mAbs are engineered to bind to two different targets simultaneously (usually to bring immune cell into contact with target cell, thereby triggering target cell killing). Antibody drug conjugate (X): toxin or radioisotope attached to mAb to increase efficacy. Asterisks denote approvals in USA only; others are approved in both USA and UK.
ADC = antibody-drug conjugate; ADCC = antibody-dependent cell-mediated cytotoxicity; ADP = adenosine diphosphate; BAFF = B-cell activating factor; CTLA-4 = cytotoxic T-cell lymphocyte associated protein-4; EGFR = epidermal growth factor receptor; HER2 = human EGFR-2; IHC = immunohistochemistry; Ig = immunoglobulin; IL = interleukin; LDL = low density lipoprotein; LDR = low density lipoprotein receptor; NSCLC = non-small cell lung cancer; PCSK9 = proprotein convertase subtilisin/kexin type 9; PDGF = platelet-derived growth factor; PD-1 = programmed cell death protein 1; PDL-1 = programmed cell death ligand 1; PML = progressive multifocal leukoencephalopathy; RA = rheumatoid arthritis; SLAMF7 = signalling lymphocyte activation molecule; TNF = tumour necrosis factor; VEGF = vascular endothelial growth factor