Nobel laureate Paul Ehrlich first proposed the concept of a “magic bullet” for cancer therapy in 1907. One century later, antibody drug conjugates (ADCs) embody this visionary concept by combining the targeting ability of monoclonal antibodies with the potent cell-killing effects of cytotoxic drugs to selectively deliver cytotoxic drugs directly to cancer cells, while sparing healthy cells.

Their promise lies in their high therapeutic index; ADCs have the potential to treat cancer at optimal dose. Systemic chemotherapy dosing by contrast is often limited due to systemic toxicities and dangerous side effects. Additionally, because they are effective in treating specific cancer subtypes, ADCs have the potential to be a valuable tool in precision oncology.

Though promising, ADCs have experienced numerous recent failures in clinical trials due to unforeseen safety challenges or lack of efficacy. More effective pre-clinical drug development processes and technologies could help to identify challenges early on and optimize selection of ADC drug candidates, increasing the likelihood of clinical success.

Striking successes

ADCs have transitioned from theoretical potential to proven therapies for patients with life-threatening diseases. Kadcyla, an ADC targeting HER2 in HER2-positive breast cancers, proved to be 47% more efficient on disease recurrence than Herceptin, the gold standard for the treatment of this type of cancer. Elahere, an ADC targeting FR-α in ovarian cancer showed a response in 42% of patients enrolled in Phase III clinical trials, whereas only 16% of patients responded to chemotherapy, nearly tripling the response rate. These successes highlight the potential of ADCs to revolutionize cancer treatment and drive the discovery and development of new ADCs.

Avoidable failures

Today more than 150 ADCs are currently in clinical trials, but recent high profiles have tempered enthusiasm ADC technologies. MEDI4276, developed for the treatment of breast or gastric cancer, failed in Phase I because of unexpected deleterious toxicities while Glembatumumab Vedotin, developed to treat osteosarcoma, failed in Phase II because of an unanticipated lack of efficacy.

Current drug discovery processes lack human systemic relevance

Traditional drug discovery technologies and animal models have proven a lack of human systemic relevance in predicting the efficacy and safety of ADCs. The broad-spectrum toxicity of ADC’s payloads makes them particularly harmful for the rest of the human body, at the systemic level, if the payload is targeted outside of the tumor site through an off-target (e.g. release of the payload in the systemic circulation) or on-target mechanism (expression of the target in healthy tissues/organs). Current in vitro methods use individual human tissues disconnected from each other, meaning these methods does not have any systemic relevance.

Unlike in vitro models, animal models provide systemic relevance since all the organs are interconnected through the systemic circulation, but they don’t provide human relevance. The high human specificity of ADCs makes preclinical studies on animals poorly translatable to the clinic, explaining unforeseen safety issues, and lack of efficacy in patients. There is a pressing need for methods that combine human and systemic relevance to reliably predict the safety and efficacy profiles of ADCs and optimize their development.

Filling the human systemic gap with new in vitro methods

Recent advancements in organ-on-chip technology offer better recapitulation of human biology. These microfluidic chips mimic the physical organization of human organs and can be connected to create systems that simulate inter-organ communication. While promising, the complexity of multiorgan-on-chip systems limits their throughput and flexibility, making them more suitable for preclinical studies rather than the initial discovery and optimization phases of ADC development. Indeed, the discovery and optimization of ADCs needs the capacity to test hundreds to thousands of compounds in human systemic conditions.

Innovative preclinical technologies can unleash the full potential of ADCs

At FluoSphera we have developed a disruptive technology platform based on tissue multiplexing to generate high-throughput in vitro systems that integrate human and systemic relevance. This platform replicates human organ environments using color-coded microtissues, allowing for the creation of multi-tissue systems within single wells of multi-well plates. High-content screening microscopy tracks these tissues to measure drug selectivity and effects in systemic conditions on thousands of wells.

FluoSphera’s technology offers enhanced predictive power for optimizing ADCs for clinical use. By simulating systems of multiple human organs, our technology can provide comprehensive safety and efficacy assessments, predicting off-target effects and systemic efficacy well before clinical trials. This approach can mitigate clinical risks, save time in developing life-saving treatments, and improve patient safety. Ultimately, FluoSphera has the potential to accelerate the launch of more ADCs, expanding the therapeutic arsenal against cancer much faster.

Contact us for a free trial or to learn more about how FluoSphera is revolutionizing ADC development and transforming cancer treatment.