Antibodies are essential to the body’s specialized search-and-destroy team that protects us from infections and cancers. As Y-shaped proteins, antibodies bind like a lock and key to foreign invaders to eliminate them1. Foreign invaders include pathogens like bacteria, fungi, parasites, and viruses. The two primary functions of antibodies are as follows: to recognize the invader with incredible specificity and activate the body's immune responses.
As such, antibodies are very powerful tools that are employed daily for the diagnosis and treatment of cancer. This article will explore two specific modifications of antibodies that make them highly potent in treating cancer—antibody drug conjugates and T-cell engaging bispecific antibodies.
When antibodies find the pathogens or cancer cells, they are tasked to destroy them. They bind to their targets with exquisite specificity. In binding to extracellular targets in cancer cells, antibodies can block signaling pathways, causing the cancer cells to stop growing and die.
Antibodies can also activate the other parts of the body's immune responses, triggering the killing of cancer cells' immune effectors. This activation of the body's immune response is why antibodies are widely used in oncology, hematology, and the treatment of infectious diseases.
For instance, the anti-CD20 antibody Rituximab has revolutionized the treatment of B-cell lymphomas in the past 25 years. Bevacizumab—an antibody against vascular endothelial growth factor—is very effective in treating colon, ovarian, and cervical cancer by blocking the growth of new blood vessels in tumors. Furthermore, antibodies against immune checkpoints, regulators of the immune response, are clinical superstars in treating multiple cancers by stimulating the immune system to kill cancer cells.
The first type of modified antibody that is extremely effective in cancer treatments is the antibody drug conjugates (ADC). These are a class of cancer therapies where antibodies are linked to drugs or even radioactive molecules. Due to their specificity, antibodies can deliver the drugs or radioactive molecules straight to the cancer cells.
Think of ADC as smart bombs designed to direct the payload specifically to their targets. The chemotherapy, or drug delivered by the ADC, is then released into the cancer cells, leading to their destruction. In some cases, the drug can then diffuse back out of the original cancer cell and kill the other cancer cells surrounding it. This is known as the bystander effect.
Certain vital attributes impact the effectiveness of the ADC. First, the antibodies selected need to bind to the cancer cells more specifically. These antibodies also should not elicit immune responses from the host, lest the immune system eliminates them. Second, the drugs should have high membrane permeability to heighten the aforementioned bystander effect. To make more powerful smart bombs, the drug to antibody ratio has to be increased to allow the delivery of more drugs to the target cell. Third, the linkers between the antibodies and the drugs should be stable so that the bombs are not released in circulation and kill healthy cells. Finally, the linkers should be designed in such a way that they are only cleaved upon entering the cancer cells.
In the initial clinical trial testing the effectiveness of this ADC, nearly all patients who had relapsed after initial treatment for Hodgkin's disease, a type of blood cancer, experienced significant shrinkage of stem cell transplants in their tumors. Current patients who had undergone stem cell transplants experienced the same experience. The high efficacy rates of Brentuximab were achieved at the expense of relatively few side effects. Some patients experienced mild diarrhea, numbness, and tingling. In a subsequent clinical trial, patients with relapsed Hodgkin's disease following stem cell transplant were assigned to either placebo or Brentuximab maintenance for about six months. The study shows that patients who received Brentuximab were cured at a much higher rate than patients who received a placebo. Due to the usefulness of ADC, a number are already adopted in routine clinical use, with a larger number in rapid development. Trastuzumab Deruxtecan, a second-generation ADC, contains a very stable linker and a high drug-to-antibody ratio of 8, double the first-generation ADCs. Trastuzumab Deruxtecan has shown unprecedented efficacy rates in treating breast cancer and is also promising in treating gastric, lung, and colon cancer.
The T-cell engaging bispecific antibodies are the second type of antibody construct that is extremely effective in cancer treatments. These are antibodies linked together to form an immunologic synapse, which brings together cancer cells and cells of the immune system, thereby inducing immune responses against the tumor. T-cell engaging bispecific antibodies such as Blinatumumab are in routine clinical, while Glofitamab has shown promising results in late-stage trials.
Blinatumumab is an anti-CD19 antibody—which binds specifically to the tumor—and an anti-CD3 antibody that brings T cells into the vicinity of the tumor cell, eliciting antigen-specific immune responses against the tumor. This is the first bispecific T-cell engager created to treat relapsed acute lymphoblastic leukemia. Patients treated with Blinatumumab after relapse had higher overall survival rates than those treated with chemotherapy.
Active in treating several B-cell lymphomas, Glofitamab is another T-cell engager antibody currently developing. In a trial involving over 300 patients, some highly resistant to conventional treatments, treatment with Glofitamab resulted in high tumor shrinkage rates.
As with other forms of immunotherapy, once a potent immune response against the tumor is induced by bispecific antibodies in the patient, the control of the tumor can be long-lasting without further treatment. This is due to the durability of the anti-tumor immune responses.
While antibodies are widely used to improve treatment outcomes in cancer, ongoing research is being carried out to enhance antibody modifications for more optimal outcomes.
