Fighting cancer with smart bullets: The antibody-drug conjugates revolution

• Antibody-drug conjugates (ADCs) hold promise in cancer therapy, targeting malignant cells via a surface protein called the Epidermal Growth Factor Receptor (EGFR).
• Creating ADCs is difficult because it involves carefully controlling drug attachment to an antibody and then drug release only in cancer cells, leaving healthy cells unharmed.
• Can more effective ADCs be developed for cancer treatment, specifically by targeting EGFR on cancer cells?
• Dr David FitzGerald and Dr Antonella Antignani at the National Cancer Institute, USA, are researching the use of the antibody ‘40H3’ to transport toxic payloads (such as Tesirine) into tumours.
• Their approach shows significant efficacy in tumour-bearing mice, offering hope for improved cancer outcomes.

Antibodies, proteins naturally produced by the immune system, play a vital role in protecting the body against a range of harmful invaders, such as bacteria and viruses – but also cancer cells. In the context of cancer therapy, these antibodies are harnessed for their unique ability to target specific molecules that are either overexpressed or abnormally present on the surface of cancer cells. Dr David FitzGerald and Dr Antonella Antignani, based at the Laboratory for Molecular Biology, Center for Cancer Research, NCI, USA, have conducted groundbreaking research in the development of antibody-drug conjugates – medications that incorporate antibodies joined with toxic payloads.

Often called ‘smart bullets’, ADCs are meticulously engineered to exclusively pinpoint cancer cells, leaving healthy cells unharmed.

These innovative drugs are designed to specifically target cancer cells and effectively eliminate them. Their research has demonstrated promising results in mouse studies, sparking optimism that more effective cancer treatments for patients are on the horizon.

The antibody

Antibody-drug conjugates (ADCs) represent specialised cancer treatments that utilise monoclonal antibodies (mAbs) to precisely target cancer cells and deliver potent cytotoxic drugs directly to these cells. This approach minimises harm to healthy tissues in our body; as such, it represents one of the most successful recent cancer treatments, with several ADCs already approved by the US Food and Drug Administration and the European Medicines Agency, and many more in clinical trials.

Often called ‘smart bullets’, ADCs are meticulously engineered to exclusively pinpoint cancer cells, leaving healthy cells unharmed. They operate with surgical precision, delivering cytotoxic drugs directly to the cancer cells. Introduced into the bloodstream, these ADCs recognise specific receptors present on cancer cells, with the Epidermal Growth Factor Receptor (EGFR) being one of the most extensively studied in the realm of oncology. Many types of cancer, such as breast, lung, colon, and brain tumours, exhibit abnormally high EGFR levels or mutations in the EGFR gene. These genetic irregularities drive the growth, survival, and spread of cancer cells. However, EGFR is not exclusive to cancer cells and is also found in normal tissues, including the skin and gastrointestinal tract lining. The presence of EGFR on both cancer and healthy cells adds complexity to the treatment of these cancers.

Choosing the right weapons

ADCs are composed of three essential components crucial for the success of the final drug: a monoclonal antibody, a cytotoxic drug called the ‘payload’, and a linker – a chemical bridge connecting the antibody to the cytotoxic drug.

FitzGerald and Antignani’s research focuses on designing ADCs that specifically target EGFR receptors on cancer cells, using the 40H3 antibody. This antibody is not naturally present in our bodies; instead, it is designed in the lab to recognise a particular region of the EGFR or EGFRvIII (an EGFR mutation which is associated with abnormal cancer cell growth).

For the payload carried by the mAb, they explored three different options: tubulin-modifying agents, topoisomerase inhibitors, and DNA-modifying agents. Tubulin-modifying agents disrupt tubulin, a critical protein involved in cell division (mitosis), leading to cancer cell death. Topoisomerase inhibitors induce breaks in DNA strands, accumulating DNA damage within cancer cells and triggering cell death. Finally, DNA-modifying agents alter the structure and function of DNA, introducing breaks or cross-linking, ultimately causing DNA damage and cancer cell death.

Concerning the linker, FitzGerald and Antignani studied four varieties to control drug release within target cells. They all share a common trait of controlled degradation upon reaching cancer cells, facilitating payload release. Some linkers are designed to be cleaved by lysosomal enzymes like cathepsins, while others are pH-sensitive, releasing the drug in response to the acidic conditions within lysosomes. The researchers’ meticulous experimentation with various linker types aims to optimise payload delivery within cancer cells, ensuring a precise and lethal effect.

Winning the battle against tumours

After assessing various payloads and linkers, FitzGerald and Antignani identified 40H3-Tesirine, an ADC featuring a valine-alanine cleavable linker within lysosomes, coupled with a potent cytotoxic drug called pyrrolobenzodiazepine (PBD) dimer – a class of synthetic compounds with potent anti-cancer properties. The researchers assessed this ADC’s effectiveness by measuring the sensitivity of different cancer cell lines with varying levels of EGFR expression.

The results demonstrated that the 40H3-Tesirine conjugate stood out as the most active and potent ADC, particularly effective against cells with high EGFR expression, such as MDA-MB-468 and BT-20, which are both typically used in breast cancer research, especially related to ‘triple-negative’ breast cancer (TNBC). As the name implies, TNBC lacks all three targets of standard treatment for breast cancer, leaving patients with few options beyond chemotherapy. The high expression of EGFR by some TNBCs provides a new opportunity for treatment, possibly with a targeted ADC such as 40H3-Tesirine.

ADCs like 40H3-Tesirine offer a promising path forward in our ongoing battle against cancer.

Further, these investigators reported that 40H3-Tesirine exhibited ‘bystander killing’, which refers to a phenomenon where the payload released has the ability to diffuse and affect neighbouring cells, including nearby cancer cells, thus maximising the cancer treatment.

Following this, the researchers tested the efficacy of 40H3-Tesirine in mice of TNBC, using MDA-MB-468 and BT-20 cells. The results were highly promising, with 40H3-Tesirine leading to complete regression of tumours in these models, with minimal signs of toxicity.

The potential of ADCs

FitzGerald and Antignani’s research on ADCs is groundbreaking in cancer therapy. Their work promises more effective and targeted cancer treatments, underlining the precision and potential of ADCs in the ongoing battle against cancer. By combining precision targeting, innovative payload delivery, and the ability to impact neighbouring cells, ADCs like 40H3-Tesirine offer a promising path forward in our ongoing battle against cancer.

In essence, the future of cancer therapy holds the promise of more targeted, less toxic treatments that not only improve patient outcomes but also redefine the entire paradigm of how we approach and ultimately cure cancer.