Clinical Applications of Monoclonal Antibodies

Monoclonal Antibodies Approved by FDA for Clinical Use

Most antibodies produced as part of the normal immune response are polyclonal, meaning that they arise from a number of distinct B lymphocytes, and, as a result, they each have a slightly different specificity for the target antigen (eg, by binding different epitopes or binding the same epitope with different affinities). However, it is possible to produce large quantities of an antibody from a single B-cell clone and when biopharmaceutical companies do this with an eye toward producing a therapeutic, these are called monoclonal antibodies.

Monoclonal antibodies work against cancer in three possible ways:

  • Activating the immune system to target malignant cells
  • Supplement the immune system by attaching to the malignant cells and preventing their interaction with growth factor biochemical signaling systems that enable proliferation of cancer.
  • Act as a delivery system to bring a radioactive atom or chemical toxin to the malignant cells.

The first monoclonal antibody used in the clinic was AB 89 against a case of Hodgkin’s lymphoma in 1983.   Below are mABs approved by the FDA for cancer treatment  Dozens of new ones are in clinical trials, both for hematologic malignancies as well as solid tumors.

Immunoglobulin G (IgG) is one of the most abundant proteins in human blood, accounting for about 10–20% of plasma protein. It is the most common protein of the five classes of immunoglobulins in human beings, IgM, IgD, IgG, IgA, and IgE.  IgG has four subclasses numbered IgG1, IgG2, IgG3, and IgG4.

Variations

Most therapeutic antibodies target only one cellular antigen; their specificity is part of their appeal, but some have two targets.  These are called bispecific monoclonal antibodies.  Only artificial antibodies are bispecific – the body’s natural immune cells have only one target.  Bispecific antibodies are sometimes called BsAbs.  Only three BsMAbs are on the market for cancer therapy: Amivantamab, Blinatumomab, and Tebentafusp.  Others are in development.  BiTEs are “bispecific antibodies T-cell engagers”; the pharmaceutical company Amgen came up with this term – it remains to be seen whether it will catch on.  The BiTEs link to both the tumor cells and to T-cells from the body’s immune system.  Blinatumomab and Tebentafusp are the only BiTEs currently approved for cancer treatment.

Medicinal chemists have even developed some trifunctional antibodies (TrAbs), which bind to three sites.  These are like bispecific antibodies that bind to antigens and also have a third link to an Fc receptor on one of the body’s immune cells.  No trifunctional antibodies are currently used in cancer treatment.

Hematologic malignancies

A number of antigens and their collateral monoclonal antibodies have been identified for the treatment of B cell malignancies. CD20, CD52 and CD22 are targets for B cell malignancies and different forms of chronic lymphocytic leukemia. Each of these antigens plays a role in B and T cell activation, proliferation, and differentiation and hence targeting them attenuates cancer cell growth.

Solid tumors

With solid tumors, cell type specificity becomes an issue as there are not many specific targets for monoclonal antibodies that are not cross-reactive with antigens on normal tissues. Trastuzumab is the most widely used monoclonal antibody against solid tumor in the US.  It has had great success against metastatic breast cancer.

Generic name (trade name)TargetAntibody FormatCancer Indication
Unconjugated antibodies    
Rituximab (Rituxan)CD20Chimeric IgG1Non-Hodgkin lymphoma, chronic lymphocytic leukemia
Trastuzumab (Herceptin)HER2Humanized IgG1Breast cancer, stomach adenocarcinoma
Alemtuzumab (Campath)CD52Humanized IgG1Chronic lymphocytic leukemia
Cetuximab (Erbitux)EGFRChimeric IgG1Colorectal cancer, non-small cell lung cancer, and squamous cell carcinoma of the head and neck
Bevacizumab (Avastin)VEGFAHumanized IgG1Colorectal, renal cell carcinoma, cervical cancer, glioblastoma, non-small cell lung cancer, and ovarian epithelial cancer.
Panitumumab (Vectibix)EGFRHuman IgG2Colorectal cancer
Ofatumumab (Arzerra)CD20Human IgG1Chronic lymphocytic leukemia
Elotuzumab (Empliciti)SLAMF7 blocker: CD 319Humanized IgG1Multiple myeloma
Necitumumab (Portrazza)EGFRHuman IgG1Non-small-cell lung cancer
Daratumumab (Darzalex)CD38Human IgG1Multiple Myeloma
Dinutuximab (Unituxin)GD2Chimeric IgG2Neuroblastoma
Olaratumab (Lartruvo)PDGFR-αHuman IgG1Solid tumors
Atezolizumab (Tecentriq)PD-L1Humanized IgG1Small cell lung cancer, urothelial carcinoma, breast cancer, non-small cell lung cancer
Avelumab (Bavencio)PD-L1Human IgG1Merkel cell carcinoma, renal cell carcinoma, and urothelial carcinoma
Belantamab mafodotin-blmf (Blenrep)BCMAHumanized IgG1Multiple myeloma
Blinatumomab (Blincyto)CD3, CD19Mouse IgG1B-cell acute lymphoblastic leukemia
Cemiplimab-rwlc (Libtayo)PD-1Human IgG4Squamous cell carcinoma
Durvalumab (Imfinzi)PD-L1Human IgG1Non-small cell lung cancer and urothelial carcinoma.
Ipilimumab (Yervoy)CTLA-4Human IgG1Melanoma and other types of cancer.
Isatuximab (Sarclisa)CD38Chimeric IgG1Melanoma, colorectal cancer, hepatocellular carcinoma, mesothelioma, non-small cell lung cancer, renal cell carcinoma.
Margetuximab (Margenza)HER2Chimeric IgG1Breast cancer
Mogamulizumab (Poteligeo)CCR4Humanized IgG1T-cell lymphoma
Naxitamab (Danyelza)GD2Humanized IgG1Neuroblastoma
Nivolumab (Opdivo)PD-1Humanized IgG4Melanoma and many other types of cancer
Nivolumab/relatlimab (Opdualag)PD-1 and LAG-3Humanized IgG4Melanoma
Obinutuzumab (Gazyva)CD20Humanized IgG1Chronic lymphocytic leukemia and follicular lymphoma.
Pembrolizumab (Keytruda)PD-1Humanized IgG4Cervical cancer, stomach cancer, and many other types of cancer.
Pertuzumab (Perjeta)HER2Humanized IgG1Breast cancer
Ramucirumab (Cyramza)VEGFR-2Human IgG1Liver cancer and others.
Siltuximab (Sylvant)G1-kappa or IL-6Chimeric IgG1Castleman disease
Tafasitamab-cxix (Monjuvi)CD19Humanized IgG1Diffuse large B-cell lymphoma
Tebentafusp-tebn (Kimmtrak)CD3 Uveal melanoma
Dostarlimab-gxly (Jemperli)PD-1Humanized IgG1Endometrial cancer
Amivantamab-vmjw (Rybrevant)EGFR and METHuman IgG1Non-small cell lung cancer
Immunoconjugates   
Brentuximab vedotin (Adcetris)CD30Chimeric human/mouse IgG1Lymphoma
Denileukin diftitox (Ontak)CD22Fusion protein IgG1Leukemia and lymphoma
Enfortumab vedotin-ejfv (Padcev)Nectin-4Human IgG1Bladder cancer
Fam-trastuzumab deruxtecan-nxki (Enhertu)HER2Humanized IgG1Breast cancer
Gemtuzumab ozogamicin (Mylotarg)CD33Humanized IgG4Acute myelogenous leukemia
Inotuzumab ozogamicin (Besponsa)CD22Humanized IgG4Lymphoma
Moxetumomab pasudotox-tdfk (Lumoxiti)GD2Mouse IgG1Hairy cell leukemia
Polatuzumab vedotin (Polivy)CD79bHumanized IgG1Lymphoma
Sacituzumab govitecan-hziy (Trodelvy)TROP-2Humanized IgG1Breast cancer
Tagraxofusp-erzs (Elzonris)CD123Fusion protein IgG1Dendritic cell neoplasm
Tisotumab vedotin-tftv (Tivdak)CD142 (Tissue factor)Human IgG1Cervical cancer
Trastuzumab emtansine (Kadcyla)HER2Humanized IgG1Breast cancer
90Y-Ibritumomab tituxeta (Zevalin)CD20Mouse IgG1Lymphoma
Lutetium Lu 177 dotatate (Lutathera)Somatostatin receptorsN/AGastroenteropancreatic neuroendocrine tumors
I-131 Tositumomab (Bexxar)CD22Mouse IgG1Lymphoma
Loncastuximab tesirine-lpyl (Zynlonta)CD19Humanized IgG1Lymphoma