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.