Engineering The Next-Generation Peptide Therapeutics

Among the most difficult targets in drug discovery are protein–protein interactions (PPIs). PPIs are essential extra- and intracellular processes that are often implicated in disease progression such as cancer, autoimmune disorders, cardiovascular diseases, inflammatory and neurodegenerative conditions. However, the very nature of PPIs—characterized by large, shallow, and dynamic binding surfaces—renders them technically challenging to disrupt with conventional small molecules. Monoclonal antibodies represent the most promising strategy in this therapeutic space, but their large size, poor permeability, low tissue penetration, and systemic clearance remain a significant challenge. This is where AdaptBio Therapeutics’ proprietary ADAPT platform (short for Adaptive Design of Antibody Paratopes into Therapeutics) originally developed by Professor Stéphane Roche at the Florida Atlantic University comes in, bridging the gap between small-molecule and antibody drugs to create a new generation of peptide therapeutics.

One major difficulty in designing such molecules is to ensure scaffold stability and proper folding since peptides often lack the structural rigidity needed to effectively mimic antibodies. Indeed, most PPI inhibitors derived from antibodies fail to maintain their active conformation when removed from their native context. Another fundamental challenge is that many PPI interfaces, such as PD1/PDL1, lack well-defined binding pockets which adds difficulty to the design of high-affinity inhibitors. Recent studies by the Roche group started to unveil the structural principles that govern the stability and folding of the complementarity-determining region H3s (CDR-H3s) found in antibodies.(1) In comparison to all other CDRs, CDR-H3 loops are known to possess the largest variability of sequence, topology, and length needed to maximize antibodies’ binding affinity and specificity. Inspired by these highly adaptable CDR-H3 loops, ADAPTins are engineered β-hairpin peptide scaffolds that retain the specificity of antibodies while overcoming their pharmacokinetic limitations. These peptides offer a game-changing approach to disrupting PPIs, enabling targeted interventions in oncology, immunology, and beyond.

“As we continue to unlock the full potential of our ADAPTin platform, our goal is to demonstrate the disruptive nature of our technology, because we have a new valuable tool in hand to streamline the synthesis of peptides never seen before” Stéphane Roche, PhD, Founder and Chief Executive Officer of AdaptBio Therapeutics.

In a recent study, the team of researchers at Florida Atlantic demonstrated that ADAPTins can effectively inhibit the PD1/PDL1 immune checkpoint interaction, a key target in cancer immunotherapy. Unlike traditional antibodies, which require intravenous administration and have long half-lives, ADAPTins are designed for improved tissue penetration and bioavailability, making them viable candidates for subcutaneous delivery. Moreover, by incorporating covalent warheads, the team developed irreversible inhibitors, ensuring long-lasting therapeutic effects. (2) Beyond oncology, this scaffold technology is unlocking new frontiers in intracellular drug delivery. Traditionally, peptide-based therapeutics have struggled to cross cell membranes, limiting their application to extracellular targets. However, these researchers have shown that designed β-hairpin peptides can achieve passive membrane permeability, opening the door to intracellular PPI inhibitors. (3) The results showed that several of these large β-hairpin peptides successfully crossed artificial membranes, despite their size far exceeding the limits set by Lipinski’s “rule of five,” which typically predicts poor permeability for large molecules. A circular dichroism study provided another clue that these peptides changed their structure when moving from water to lipid environments, suggesting their ability to dynamically adjust their shape to cross membrane efficiently. This study has profound implications for tackling diseases driven by intracellular interactions, such as inflammatory diseases, viral infections (HIV, SARS-CoV-2) and potentially neurodegenerative disorders (Alzheimer’s, Parkinson’s). Indeed, we believe these studies represent more than just a step forward—it is a shift toward a new wave of biologically inspired peptides following the footsteps of cyclic β-sheets (Spexis), helices (Parabilis Medicines), and bicyclic peptides (Bicycle Therapeutics) to deliver smaller, more potent, and more precise than ever before peptide therapeutics.

These discoveries have real-world needed applications that could advance biotechnology and medicine. One particularly promising area is in biosensors and diagnostic tools where ADAPTins could be used to develop highly selective molecular probes, allowing clinicians to detect biomarkers with incredible accuracy even in complex biological samples. In oncology, these engineered peptides might pave the way for the next generation of immune checkpoint blockers, providing new alternatives to existing drugs like pembrolizumab and nivolumab. Unlike some antibodies, ADAPTins might be formulated for subcutaneous delivery, making them not only affordable, effective, but also more accessible to patients.

“Ongoing studies will deepen our current understanding of CDR-H3 loop structures and open doors for designing synthetic antibody fragments, which could serve as more economical and more scalable alternatives to monoclonal antibodies.” Stéphane Roche, CEO of AdaptBio Therapeutics.

By engineering some the best attributes of antibodies into small molecules, AdaptBio’s ADAPTins promise a new class of therapeutics that are smaller, more stable, and highly targeted. The company is actively developing anti-PD(L)1, anti-CD20/CD40, and anti-IL4a/IL17a/F inhibitors, targeting diseases with high unmet medical needs. Furthermore, AdaptBio Therapeutics is also pioneering peptide-based vaccines, leveraging the adaptability of its platform to create constrained epitopes embedded in hairpin peptides. Whether in oncology, immunology, or inflammatory diseases, AdaptBio is taking on the race to transform these novel peptide therapeutics into the drugs of tomorrow.