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 two BsMAbs are on the market for cancer therapy: Amivantamab and Blinatumomab..  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 is the only BiTE 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) Target Antibody Format Cancer Indication
Unconjugated antibodies      
Rituximab (Rituxan) CD20 Chimeric IgG1 Non-Hodgkin lymphoma, chronic lymphocytic leukemia
Trastuzumab (Herceptin) HER2 Humanized IgG1 Breast cancer, stomach adenocarcinoma
Alemtuzumab (Campath) CD52 Humanized IgG1 Chronic lymphocytic leukemia
Cetuximab (Erbitux) EGFR Chimeric IgG1 Colorectal cancer, non-small cell lung cancer, and squamous cell carcinoma of the head and neck
Bevacizumab (Avastin) VEGFA Humanized IgG1 Colorectal, renal cell carcinoma, cervical cancer, glioblastoma, non-small cell lung cancer, and ovarian epithelial cancer.
Panitumumab (Vectibix) EGFR Human IgG2 Colorectal cancer
Ofatumumab (Arzerra) CD20 Human IgG1 Chronic lymphocytic leukemia
Elotuzumab (Empliciti) SLAMF7 blocker: CD 319 Humanized IgG1 Multiple myeloma
Necitumumab (Portrazza) EGFR Human IgG1 Non-small-cell lung cancer
Daratumumab (Darzalex) CD38 Human IgG1 Multiple Myeloma
Dinutuximab (Unituxin) GD2 Chimeric IgG2 Neuroblastoma
Olaratumab (Lartruvo) PDGFR-α Human IgG1 Solid tumors
Atezolizumab (Tecentriq) PD-L1 Humanized IgG1 Small cell lung cancer, urothelial carcinoma, breast cancer, non-small cell lung cancer
Avelumab (Bavencio) PD-L1 Human IgG1 Merkel cell carcinoma, renal cell carcinoma, and urothelial carcinoma
Belantamab mafodotin-blmf (Blenrep) BCMA Humanized IgG1 Multiple myeloma
Blinatumomab (Blincyto) CD3, CD19 Mouse IgG1 B-cell acute lymphoblastic leukemia
Cemiplimab-rwlc (Libtayo) PD-1 Human IgG4 Squamous cell carcinoma
Durvalumab (Imfinzi) PD-L1 Human IgG1 Non-small cell lung cancer and urothelial carcinoma.
Ipilimumab (Yervoy) CTLA-4 Human IgG1 Melanoma and other types of cancer.
Isatuximab (Sarclisa) CD38 Chimeric IgG1 Melanoma, colorectal cancer, hepatocellular carcinoma, mesothelioma, non-small cell lung cancer, renal cell carcinoma.
Margetuximab (Margenza) HER2 Chimeric IgG1 Breast cancer
Mogamulizumab (Poteligeo) CCR4 Humanized IgG1 T-cell lymphoma
Naxitamab (Danyelza) GD2 Humanized IgG1 Neuroblastoma
Nivolumab (Opdivo) PD-1 Humanized IgG4 Melanoma and many other types of cancer
Obinutuzumab (Gazyva) CD20 Humanized IgG1 Chronic lymphocytic leukemia and follicular lymphoma.
Pembrolizumab (Keytruda) PD-1 Humanized IgG4 Cervical cancer, stomach cancer, and many other types of cancer.
Pertuzumab (Perjeta) HER2 Humanized IgG1 Breast cancer
Ramucirumab (Cyramza) VEGFR-2 Human IgG1 Liver cancer and others.
Siltuximab (Sylvant) G1-kappa or IL-6 Chimeric IgG1 Castleman disease
Tafasitamab-cxix (Monjuvi) CD19 Humanized IgG1 Diffuse large B-cell lymphoma
Dostarlimab-gxly (Jemperli) PD-1 Humanized IgG1 Endometrial cancer
Amivantamab-vmjw (Rybrevant) EGFR and MET Human IgG1 Non-small cell lung cancer
Immunoconjugates      
Brentuximab vedotin (Adcetris) CD30 Chimeric human/mouse IgG1 Lymphoma
Denileukin diftitox (Ontak) CD22 Fusion protein IgG1 Leukemia and lymphoma
Enfortumab vedotin-ejfv (Padcev) Nectin-4 Human IgG1 Bladder cancer
Fam-trastuzumab deruxtecan-nxki (Enhertu) HER2 Humanized IgG1 Breast cancer
Gemtuzumab ozogamicin (Mylotarg) CD33 Humanized IgG4 Acute myelogenous leukemia
Inotuzumab ozogamicin (Besponsa) CD22 Humanized IgG4 Lymphoma
Moxetumomab pasudotox-tdfk (Lumoxiti) GD2 Mouse IgG1 Hairy cell leukemia
Polatuzumab vedotin (Polivy) CD79b Humanized IgG1 Lymphoma
Sacituzumab govitecan-hziy (Trodelvy) TROP-2 Humanized IgG1 Breast cancer
Tagraxofusp-erzs (Elzonris) CD123 Fusion protein IgG1 Dendritic cell neoplasm
Tisotumab vedotin-tftv (Tivdak) Cervical cancer
Trastuzumab emtansine (Kadcyla) HER2 Humanized IgG1 Breast cancer
90Y-Ibritumomab tituxeta (Zevalin) CD20 Mouse IgG1 Lymphoma
Lutetium Lu 177 dotatate (Lutathera) Somatostatin receptors N/A Gastroenteropancreatic neuroendocrine tumors
I-131 Tositumomab (Bexxar) CD22 Mouse IgG1 Lymphoma
Loncastuximab tesirine-lpyl (Zynlonta) CD19 Humanized IgG1 Lymphoma