Anti-tumor Monoclonal Antibodies. New way to Fight Cancer

Releasing the Brakes: Negative Checkpoint Inhibitors

The immune system is a powerful force, but it has built-in safety measures called checkpoints to prevent it from becoming overactive and attacking healthy tissues.

Some cancer cells have cleverly learned to exploit these checkpoints, effectively putting the brakes on the immune response and allowing themselves to grow unchecked.

Negative checkpoint inhibitors are a revolutionary class of monoclonal antibodies that work by blocking these inhibitory signals, essentially releasing the brakes on the immune system and allowing it to recognize and destroy cancer cells.

These antibodies work by targeting specific checkpoint proteins. By binding to these proteins, the antibodies prevent them from being activated by cancer cells, thereby unleashing the full power of the immune system against the tumor.

Some of the key therapeutic targets for negative checkpoint inhibitors include:

• CTLA-4 (Cytotoxic T-Lymphocyte-Associated Protein 4). This was one of the first immune checkpoints to be targeted. Ipilimumab, a CTLA-4 inhibitor, was the first drug of its kind to be approved and has shown significant success in treating advanced melanoma.
• PD-1 (Programmed Cell Death Protein 1). This protein is found on the surface of T-cells, a type of immune cell that plays a central role in killing cancer cells. When PD-1 binds to its partner protein, PD-L1, on a cancer cell, it signals the T-cell to stand down. Nivolumab and Pembrolizumab are two key representatives of this group.
• PD-L1 (Programmed Death-Ligand 1). This protein is often found in high levels on the surface of cancer cells and acts as a “don’t eat me” signal to the immune system.
• LAG-3 (Lymphocyte-Activation Gene 3). This is another checkpoint protein that can suppress the activity of T-cells.
• TIM-3 (T-cell Immunoglobulin and Mucin-domain Containing-3). This target is also involved in T-cell exhaustion and is being explored as a potential therapeutic target.
• TIGIT (T-cell Immunoreceptor with Ig and ITIM domains). This is another inhibitory receptor on immune cells that is being investigated as a target for cancer immunotherapy.

Orchestrating Cell Suicide: Inducers of Cancer Programmatic Death (Apoptosis)

One of the hallmarks of cancer is its ability to evade apoptosis, the natural process of programmed cell death that eliminates old or damaged cells.

Monoclonal antibodies can be engineered to directly trigger this self-destruct mechanism within cancer cells. This can be achieved through several approaches, utilizing different types of monoclonal antibodies.

Naked Monoclonal Antibodies. These are the most common type of monoclonal antibodies and work without any other drugs attached to them. Some naked antibodies, upon binding to a specific antigen on a cancer cell, can initiate a cascade of signals within the cell that ultimately leads to apoptosis. For example, some antibodies can disrupt signaling pathways that are essential for the cancer cell’s survival, effectively pushing it towards self-destruction.

Bispecific Monoclonal Antibodies. These are innovative antibodies designed to bind to two different targets simultaneously.

A bispecific antibody can be engineered to bind to both a cancer cell and a cytotoxic immune cell, such as a T-cell. This creates a bridge between the two cells, bringing the immune cell into proximity to the cancer cell and activating it to release cytotoxic substances that induce apoptosis in the tumor cell.

Blinatumomab is an example of a bispecific antibody that has shown significant success in treating certain types of leukemia by connecting T-cells to cancerous B-cells.

Taclistamab is an extremely promising medication against multiple myeloma, designed to bridge the CD3 T-cell and the myeloma cell, activating the release of cytotoxic chemicals that destroy the tumor cell.

Antibody-Drug Conjugates (ADCs). These are monoclonal antibodies that are chemically linked to a potent anti-cancer drug, essentially acting as a guided missile to deliver a toxic payload directly to the tumor.

The antibody part of the ADC specifically seeks out and binds to cancer cells. Once attached, the ADC is often internalized by the cancer cell, releasing the chemotherapy drug inside where it can induce apoptosis and kill the cell from within. This targeted delivery helps to minimize damage to healthy cells, potentially reducing the side effects associated with traditional chemotherapy.

Halting Proliferation: Cancer Growth Blockers

Uncontrolled cell growth is a fundamental characteristic of cancer. Many types of cancer are driven by faulty signaling pathways that constantly tell the cells to divide and multiply. Monoclonal antibodies can intervene in this process by acting as “growth blockers.” They achieve this by binding to specific receptors on the surface of cancer cells that are involved in stimulating cell growth.

Two of the most prominent targets for this type of therapy are the Human Epidermal Growth Factor Receptor 2 (HER2) and the Epidermal Growth Factor Receptor (EGFR).

Targeting HER2: The HER2 protein is a receptor that, when overexpressed on the surface of cancer cells, can lead to aggressive tumor growth. This is particularly common in certain types of breast and stomach cancers. Monoclonal antibodies like trastuzumab and pertuzumab are designed to bind to the HER2 receptor. This binding can block the receptor from being activated, thereby inhibiting the downstream signaling pathways that drive cell proliferation. Furthermore, some anti-HER2 antibodies can flag the cancer cells for destruction by the immune system.

Targeting EGFR: The EGFR is another receptor that plays a crucial role in cell growth and is often overactive in various cancers, including colorectal, head and neck, and lung cancers. Monoclonal antibodies such as cetuximab and panitumumab work by binding to the extracellular domain of the EGFR. This prevents the natural ligands (molecules that activate the receptor) from binding and initiating the signaling cascade that leads to cell growth and division. By blocking this pathway, these antibodies can effectively slow down or stop tumor growth.

Cutting Off the Supply Lines: Inhibitors of Angiogenesis

For a tumor to grow beyond a certain size, it needs its own blood supply to receive oxygen and nutrients. The process of forming new blood vessels is called angiogenesis. Cancer cells can stimulate angiogenesis by releasing certain growth factors. Monoclonal antibodies can thwart tumor growth by inhibiting this process, effectively cutting off the tumor’s supply lines.

The primary target for anti-angiogenic monoclonal antibodies is a protein called Vascular Endothelial Growth Factor (VEGF). VEGF is a key driver of angiogenesis, and many tumors produce high levels of it.

Bevacizumab is a well-known monoclonal antibody that targets VEGF. It works by binding to circulating VEGF in the bloodstream, preventing it from reaching its receptors on the surface of endothelial cells (the cells that line blood vessels). By neutralizing VEGF, bevacizumab inhibits the formation of new blood vessels that are essential for tumor growth and survival.

While VEGF is a major focus, researchers are also exploring novel antibodies that target other components of the angiogenesis pathway. For instance, antibodies that block the VEGF receptors (VEGFR-1 and VEGFR-2) are in development. Ramucirumab, which targets VEGFR-2, is one such example. The idea is that by blocking the receptor itself, even if VEGF is present, it cannot deliver its pro-angiogenic signal.

By understanding these diverse and sophisticated mechanisms of action, we can appreciate the immense potential of monoclonal antibodies in the ongoing fight against cancer. These therapies represent a significant leap forward in precision medicine, offering hope for more effective and less toxic treatments for a wide range of cancers.