Since their premier on the scene, monoclonal antibodies (mAb) have demanded top billing on the biotech marquee, creating a cast of therapeutics used to treat diseases like autoimmune disorders and cancer. The first player debuted in 1986 when Janssen-Cilag’s OKT3 gained FDA approval to treat transplant rejection patients.
Fast forward to 2013, where half of the top ten best selling drugs worldwide happened to be mAbs: Avastin, Herceptin, Humira, Remicade, and Rituxan. And don’t hold back the applause, because the FDA approved four new mAbs this year. Eli Lilly’s Cyramza takes a punch to stomach cancer. Janssen’s Sylvant is reigning in Castleman’s disease – a rare disorder similar to lymphoma. Takeda’s Entyvio delivered a double knockout, treating both ulcerative colitis and Crohn’s disease. Rounding out the end of the pack is Merck’s Keytruda, putting the blinders on melanoma.
Here at WEEKLY, we marvel at the multifaceted mechanisms of actions (MOA) of mAbs as they have evolved over the years. In this issue we’ll go behind the scenes and find out exactly how they manage to shine the light on treating disease.
THE FRATERNAL TWIN
The fraternal twin to the therapeutic mAb is the naturally occurring antibody, which continually marches to the frontline to defend the human body against foreign invaders. When administered, the therapeutic mAb acts as a freshly recruited soldier to alert and work with the immune system to destroy target cells such as pathogens, cancer or other diseased cells of the body.
Immune System Activation
The Y shaped mAb above alerts the immune system to send a macrophage.
The mAbs that use immune system activation as a MOA in their portfolio include Roche’s Herceptin for breast cancer and Biogen Idec’s Rituxan for lymphoma.
THE GREAT COVERUP
Receptor proteins, or proteins residing on the cell surface that receive external signals, lose their ability to internally transmit those external signals when covered up by mAbs. Blocking signaling pathways effectively work as a form of treatment in cancers where growth factor receptor activation plays a key role in turning on cell division. Blockers of receptor signaling include Amgen’s Vectibix for colorectal cancer and Bristol-Myers Squibb’s Yervoy for melanoma.
Cell Signal Blocking
The Y shaped mAb above blocks the transmission of external signals.
mAbs also cover up signaling molecules directly – capturing the signaling molecule itself and tethering it down before it can reach the receptor. Roche’s Avastin is roping in a variety of cancers while GlaxoSmithKline’s Benlysta is tamping down the out of control immune reaction in lupus.
STOP, WHO GOES THERE?
Meet the sentry mAbs, denying infectious pathogens from gaining entry to the portals of their target cells. The life goal of pathogens are to gain entry in to the host via attachment to the surface of the target cell. The link between pathogens and host cells can be prevented – courtesy of a mAb attaching to the area on the pathogen that interacts with the host cell, blocking admittance.
Denying Viral Entry
The above virus’s attempt to enter the host cell is denied thanks to a mAb.
Astra Zeneca’s Synagis is guarding the gates against respiratory syncytial virus. It prevents viral infection by binding to proteins on the surface of a respiratory virus, stopping the potentially lethal virus in its tracks.
Increasingly, mAbs are being used as couriers to deliver a toxic drug to target cells – known as antibody-drug conjugates. In this application, a highly toxic compound is chemically attached to a mAb that recognizes proteins on the surface of a cancer cell. Once bound, the deadly payload is internalized and delivered to the innards of the tumor cells. This trojan horse treatment is less toxic because it is only delivered to the cancer cells, leaving the neighboring healthy cells in the patient’s body relatively unharmed.
Toxic Drug Distribution
The toxic “drug bomb” attached to the mAb above successfully annihilates the target cell.
While several antibody-drug conjugates are in the midst of development, only two antibody-drug conjugates have made it to market. Roche’s Kadcyla is bumping out breast cancer while Seattle Genetics’ Adcetris mutes the cancerous lymphocytes in lymphoma.