Harnessing antibody-drug conjugates (ADCs) in oncology: Pathways to clinical success

The ADC landscape has evolved significantly with treatments now approved for breast, lung, and hematologic cancers. ADCs combine monoclonal antibody precision with the potency of cytotoxic drugs. Their therapeutic potential has broadened with advancement in linker technology and payload optimization, vastly improving ADC efficacy and safety.

ADC’s ability to selectively target cancer cells works by binding to specific antigens, delivering cytotoxic agents to malignant cells while sparing healthy tissue. This aids in reducing conventional chemotherapy’s side effects, assigning ADCs as a viable option for advanced or drug-resistant cancers.

As ADC technology undergoes refinement, the scope of targetable cancers expands. The hope is that next-generation ADCs can effectively go on to develop personalized oncology therapies that can treat previously untreatable tumors.

ADC’s mechanism of action

The ingenuity of ADCs’ mechanism centers on delivering cytotoxic agents to cancer cells that link a monoclonal antibody to a payload via a specialized linker. By engineering ADCs to bind to antigens expressed on cancer cells, tumor specificity is enhanced, and healthy tissues are bypassed.

“The challenge with some ADCs is that their antibodies target specific human proteins, which don’t always have an equivalent in standard animal models. As a result, non-human primate studies are often the only available predictor.” 

The use of selective antibodies and tumor-specific linkers further enhances ADC precision which extends to overcoming drug-resistance mechanisms. ADCs introduce cytotoxins that avoid resistance pathways like multidrug resistance 1 (MDR1)-related drug efflux pumps, precisely into tumor cells. 

“By avoiding these pumps, the toxic payload can accumulate within resistant cells, resulting in cell death,” added Dr. Barnett, who then discusses first-generation ADC limitations, and their limited efficacy caused by unstable linkers and less-specific targeting.

“Early ADCs targeting solid tumors failed due to a lack of differences in payload types or attached chemotherapies. Now we’re approaching 2-3 dozen payload types in development, creating greater diversity in the mechanisms of action (MOA) and broadening ADC capabilities.

“There’s also engineering around the conjugate. When the cancer cell consumes the ADC, it leaves a little residual piece of the conjugate that may help the drug kill the cell. It’s then able to migrate to cancer cells around it. This is the bystander effect,” he added. 

“So, the two main advancements are the development of new or better payloads and innovative strategies to improve the ability of ADCs to kill cancer cells in the surrounding area via the bystander effect.”

Later generations with enhanced linker stability, optimized drug-to-antibody ratios, and potent payloads have increased the therapeutic indices and reduced off-target effects. Further elaboration was provided by Dr. Barnett regarding the significance of the therapeutic index in the context of certain types of ADC toxicity.

“ADCs can’t perfectly target a tumor-specific cell surface receptor. As a result, regardless of the antibody chosen, ADCs will, by default, enter some non-cancerous cells. When ADCs reach the clinical stage, this off-target toxicity can present challenges, potentially limiting ADC development and reducing efficacy.”

The clinical promise of ADCs in cancer treatment

As of 2024, there were 15 ADCs approved by the FDA, including Elahere (mirvetuximab soravtansine), targeting FRα-positive ovarian cancer, and Enhertu (fam-trastuzumab deruxtecan-nxki) for HER2-positive breast and gastric cancers. 

But while success is recognized, researchers still face challenges in refining ADCs. For example, ensuring tests like next-generation sequencing (NGS) are incorporated into practice patterns. By looking at gene mutations, deeper insights can be gained in selecting patients for clinical trials.

“Convincing researchers to order an extra test to assess patient trial eligibility is probably the biggest challenge,” said Dr Barnett. “ADCs trials are not more mechanistically or operationally challenging to run. Whether it’s an ADC or small molecule targeting a mutated kinase, finding and testing biomarkers are needed. If they’re not on a standard panel, the challenge is to carry out that extra test.”

Dose optimization after initial dose-finding studies also remains an ongoing challenge, rendering the task of balancing effective dosing with safety difficult. The challenges are further augmented with limited data on biomarkers and the ongoing threat of drug resistance. 

“The first solid tumor ADCs to get approved was for HER2+ metastatic breast cancer,” said Dr Barnett. “It was built on an antibody already being used so there was familiarity. The tumors that responded to that antibody were recognized so a conjugated drug worked very well.

“That leads to another way that may improve ADC activity – increasing the drug-to-antibody ratio (DAR). As these newer ADC generations enter the clinic, we’ll see novel targets and different antibodies not used by themselves. So, more testing is needed to identify tumors that are expressing the molecule.

“That may change the diagnostic side of clinical practice. It’ll take time for that to become standard. As long as the payload class differs to the standard of care, that’s a way to address drug resistance.”

ADC’s regulatory pathway

Collaborating across regulatory, clinical, and research divisions requires alignment on priorities to keep ADC development on track. Without careful coordination, differing goals can introduce complexity that may affect timelines and increase costs due to protocol adjustments or additional trials. 

Referring to his collaborative experience in the commercial launch of the first ever ADC FDA approved for breast cancer, Dr Barnett describes the manufacturing process as taking “about 18 months.”

“We tracked the product as going back and forth across the Atlantic six to eight times,” he said. 

“The Gantt chart used to track progress from drug candidate to first in human identified close to 30 different lanes. Every step was regulated, with the FDA or EMA having oversight of that. 

“So, understanding the timing, critical path components and then correlating that with the contracting work at the sites, clinical trial site and CRO selection should start 2-3 years sooner. 

“Once the Investigational New Drug (IND) clears, there will be a site patients can be enrolled in as opposed to starting the process with an IND but not having a patient enrolled for six months, which would be terrible as patients would not have access to new therapeutics.”

Future ADC outlook in oncology

As oncology moves toward more personalized treatment, ADCs offer the potential for targeted approaches that align with the demand for solutions that are both effective and minimize side effects. 

“As diagnostic techniques improve, we’re moving toward more targeted therapies, in contrast to the ‘shotgun’ approach of untargeted chemotherapy,” said Dr. Barnett. ”The future will be particularly interesting in how clinical trials evolve to help inform physician decision-making about drug sequencing, potentially supplemented by real-world evidence.”

As diagnostics advance to identify specific tumor targets, ADCs are also demonstrating potential in combination therapies, where they complement standard-line treatments that count immunotherapy and kinase inhibitors amongst their arsenal.

“From my time with small molecule kinase inhibitors,” Dr. Barnett continued, “I’ve seen that in certain ADCs, the internalized receptor complex can be recycled to the cell surface or directed to structures like the lysosome. When the cell receptor undergoes ubiquitination,  it is more effectively targeted to the lysosome, which could improve lysosomal trafficking and lead to greater payload delivery.”

By enhancing cellular targeting mechanisms, ADCs increase the efficacy of combination regimens and serve as a key component in overcoming resistance and improving the outlook for patients with aggressive or refractory cancers.

“Manufacturing is now more geographically streamlined,” Dr. Barnett noted. “This improves timelines, enabling the identification of more targets and thus more antibodies. Target diversity is also advancing, with more payload types and improved conjugation methods, making the process both more efficient and more cost-effective.”

“This year, ADC investment surpassed other oncology investments compared to last year,” Dr. Barnett added. “In the US, the Inflation Reduction Act (IRA) helps address the high manufacturing costs of ADCs by extending market exclusivity for biologics. I think regulators recognized that these novel drugs, which improve the therapeutic index, require significantly more investment to reach the clinic.”

ADC cancer therapy: A more personalized option

ADCs represent cutting-edge innovation in oncology, embodied by the advancements made in linker technology, cytotoxic payloads, and antibody engineering.

The delicate balance between toxicity and efficacy appears key to clinical success as ADCs can still cause side effects. As the pace of research gathers momentum, optimizing the choice of patient selection along with upgrading ADC design are the central themes in maximizing therapeutic potential. 

The formation of partnerships continues to prove fruitful in unlocking new pathways for ADCs, with the rise in collaborations between pharmaceutical organizations, clinical researchers, and oncologists contributing to the transformation of standard cancer care. 

Next-gen ADCs are already demonstrating promising trial results, paving the way for targeted, less invasive options that could lead to longer survival rates and improved quality of life for cancer patients.

“At the end of the day, this is all about helping patients,” concluded Dr Barnett. “We’ve gone from administering toxic, untargeted drugs with a 10-15% response rate to seeing ADCs effectively target tumors, with even low receptor expression, outperforming traditional chemotherapy.”

To learn more about ADCs, listen to Allucent’s podcast Advancing Oncology Research: Regulatory & Development Path for ADCs & Radionuclide Conjugates | Allucent or watch the recent webinar Advancing Precision Oncology: Radionuclide Conjugate and Antibody-Drug Conjugate (ADC) Development Strategies | Allucent.

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