Attack Of The Mono- & Polyclonals

Monoclonal antibody (mAb) therapeutics burst onto the healthcare scene twenty years ago. They remain one of the most versatile and effective therapies available for a whole range of diseases including different types of cancers, autoimmune diseases, infectious diseases, and most recently, even high cholesterol. Tried and true mAbs, such as Herceptin and Rituxan, remain in high demand. More on those below.

Biotech companies have built on the success of this first wave of mAbs to develop new, innovative products that deliver an even bigger punch. This WEEKLY reviews the basics of monoclonal antibodies and highlights some recent innovations.

Just The Facts

  • Antibodies are proteins produced by B-cells, a type of white blood cell. An antibody’s shape corresponds to a unique target, typically a protein on the surface of a virus or other pathogen. Scientists call these foreign proteins antigens.
  • When an antibody recognizes its particular antigen, it binds to it. The action alerts the attack cells of the immune system such as macrophages and killer T-cells, which then eliminate the pathogen.
  • The bit of the antigen the antibody locks onto is an epitope.

Antibodies’ amazing ability to recognize and bind to unique epitopes makes them highly effective therapeutics. Researchers have capitalized on this “bindability” in a number of ways. For example, scientists may identify an antibody that binds to a cancer cell antigen. When the antibody is injected into a patient, this binding prods the patient’s immune system to attack the cancer. This is the mechanism of action used by Herceptin (Roche; Basel, Switzerland) to attack HER2-positive breast cancer, and by Rituxan (Roche) to attack non-Hodgkin’s lymphoma and chronic lymphocytic leukemia.

Easily Confused: Monoclonal vs. Polyclonal Antibodies

Antibodies come in two types. Monoclonal antibodies all derive from the same B-cell, or its clones (descendants). This enables them to recognize the same epitope. Therapeutic antibodies are always monoclonal, which ensures consistent treatment.

Polyclonal antibodies are produced by a collection of different B-cells. As a result, they recognize multiple epitopes on the same antigen, which makes them ideal for some kinds of diagnostics and research, where the only requirement is detecting a specific antigen.

New & Improved Y

Fun fact: antibodies are Y-shaped. In antibodies produced naturally by our bodies and in most therapeutic antibodies, the two “arms” of the Y are identical and recognize only one target.

In contrast, bispecific antibodies have been genetically engineered by splicing genes for two different monoclonal antibodies to make a new Y. This way, the bispecific antibody is able to recognize two different targets and bring them in contact with one another.

Imagine that one arm of the Y recognizes a cancer cell.  Meanwhile, the other arm recognizes and binds to a killer T-cell. Remember, killer T’s are white cells that inject toxins directly into cells. By bringing the malignant cell it “caught” into contact with a killer T-cell, the first arm of the Y essentially forces the killer-T-cell into action — killing the cancer cell.

The cool thing is that it’s not even necessary to imagine this scenario — it’s the mechanism that Blincyto (Amgen; Thousand Oaks, CA) uses.

So far only two bispecific antibodies have been approved by the FDA: Blincyto and Roche’s (Basel, Switzerland) Hemlibra, approved to treat hemophilia A. Hemlibra works by bringing together blood clotting factors IX and X, enabling the activation of factor X. In healthy people, factor X is activated by clotting factor VIII, but hemophilia A patients lack this factor.

The ABCs Of ADCs

Another type of game-changing innovation in mAb technology is antibody-drug conjugates (ADCs): highly-potent, targeted therapeutics that combine the targeting power of monoclonal antibodies with the cancer-killing ability of toxic drugs. This potent combo can destroy cancer cells with less impact on healthy cells.

ADCs have three key components:

  • A monoclonal antibody that is highly specific for a tumor-associated antigen with little to no expression on healthy cells.
  • A highly toxic small molecule drug to kill the cancer cell once internalized.
  • A chemical linker that connects the small molecule drug to the antibody. The linker is stable in a person’s bloodstream, releasing the drug once inside the tumor.

How does this work?

  1. The antibody binds to its target antigen on the cancer cell surface.
  2. The antibody-drug conjugate is then taken up – internalized – by the cell.
  3. Once inside the malignant cell, the linker degrades and the active drug is released.

The ability to target only cancer cells allows doctors to administer much more toxic medicines than with traditional chemotherapy. This is because the ADC’s precision means it avoids healthy tissue that chemotherapy often damages or destroys.

There are currently four ADCs on the market:

  • Seattle Genetics’ (Seattle, WA) Adcetris for Hodgkin’s lymphoma
  • Roche’s Kadcyla for HER2-positive breast cancer
  • Pfizer’s (New York, NY) Besponsa for acute lymphoblastic leukemia
  • Mylotarg, also by Pfizer, for acute myeloid leukemia.

The next WEEKLY continues our foray into next-generation antibodies with a look at photoimmunotherapy and nanobodies.

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