Identifying Optimal Targets for Antibody Drug Conjugates (ADCs)

This is the fourth in a four-part series about challenges and best practices in developing Antibody-Drug Conjugates, or ADCs.

Because of the improved benefit/risk balance in recent years, we are seeing enormous activity in Phase I and Phase II studies for ADCs, many of which we expect to move into Phase III. These treatments are poised to reshape the landscape of cancer therapy. Improvements in linker technology have enabled us to decrease off-target toxicity considerably. Now, the drug linker technology can deliver the payload better to the target, whereas before, this toxic payload could dissociate from the linker and antibody and be free-floating in the body causing considerable toxicity. Moreover, thanks to advances in biomarker technology, we are now better able to identify the optimal targets that are highly expressed on tumors but minimally expressed on normal tissue cells.

Potential solutions

However, identifying optimal targets continues to be a challenge. Several solutions are enabling researchers to make progress, including advanced genomics and proteomics, and screening techniques to identify novel tumor-specific antigens. It is essential to develop ADCs against multiple epitopes of the same target to increase specificity. Higher tumor selectivity can potentially be achieved through antigen engineering, such as masked antibodies, to minimize systemic toxicity.

We recommend considering targets in two specific metabolic pathways, where we are seeing increased acuity. Considering the heterogeneity of the target expression and the variability in the target antigen expression with tumors and across patients, a possible solution is to develop appropriate companion diagnostics. With this approach, the ADC is combined with other targeted therapies or immunotherapies to identify patients most likely to benefit. This will of course involve thorough pre-clinical studies to identify synergic combinations, along with careful dose-escalation strategies using pharmacokinetics/pharmacodynamics (PK/PD) modeling.

With each of these approaches, seamless and adaptive trial designs can provide the flexibility to make changes based on new information collected. While planning adaptive protocols can add time to the schedule, you can feasibly go to market with a single clinical study, saving you money and time during the development of your product.

As a final note on combination therapies: If the combination product drug is already approved, you can consider running the combination trials in parallel with monotherapy dose escalation – for example, after dose levels 2 and 3 have been cleared without dose-limiting toxicity. If the combination drug is not approved, you can start the combination dose escalation after the completion of the monotherapy dose. To improve tolerability, for example, instead of combining the ADC with the PD-1 inhibitor, sequential dosing can better manage toxicities than a concurrent approach. Regulators may request different treatment schedules to better understand the safety/benefit-risk balance of each regimen.

Biomarker plans

Advances in biomarker science and technology are another important factor in the potential for combination therapies. In fact, biomarker development should be incorporated into discovery efforts early in the process. We can use multiomics approaches to identify comprehensive biomarker features – also fundamental for pinpointing the patient population most likely to benefit from the treatment. Regulators will expect thorough biomarker analysis during post-approval and, increasingly, even pre-approval. Note that both the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have tightened their requirements in this area in recent years.

Post-marketing surveillance

In addition, regulators are likely to request extended follow-up periods because of the risk of late toxicities. Besides those required, we recommend implementing additional post-marketing surveillance programs. Every drug has side effects; what’s important is to demonstrate to regulators that the safety profile is clinically manageable. In that regard, we also recommend registries for long-term tracking of patients treated with ADCs.

Clearly, given the changing regulatory landscape, your overall development plan should encompass monitoring of policies and the flexibility to adapt your technical development plan accordingly. Further, we recommend early engagement with regulators and consultation with them at critical decision points.

How we can help

Our strong team of commercial strategists, clinicians, former regulators, and market access experts can partner with you to de-risk your drug development and illuminate the path to commercial success. It is an exciting time for the industry, and we look forward to joining you in the journey to bring important innovations to patients. 

Parexel Biotech offers the personal, responsive, and committed approach of a small CRO, with all the benefits of a large CRO, to help you develop life-changing treatments for patients.

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