Bring Your Candidate Peptide to the Next Level with Lead Optimization

Increasing Peptide Drug Potency through Microarray Screening Technology

Most peptides identified as lead or candidate-lead in a screening campaign show interesting yet suboptimal properties compared to a full-grown therapeutic drug. Typical target affinities of these leads are usually ~100-1000 times too low, and their stabilities to enzymatic degradation are still insufficient. This, alongside in vivo half-life and bioavailabilities, should be optimized.

Pepscan designs the most efficient and economical libraries for our customers and provides a full list of peptide sequences. If the 3D conformation of the peptide is important for activity, we also provide libraries of 3D-constrained (CLIPS™) peptides. A wide range of peptide libraries is made available, each tailored to specific research needs. In the following paragraphs, you can read more about our past achievements.

Case 1: Diagnostics for Multiple Sclerosis (MS)

Pepscan collaborated with the US company Abreos Biosciences to optimize 3 structurally related lead SS peptides as selective binders for the monoclonal antibody Natalizumab. These leads were identified in the past by phage-display peptide-library screening. Replacement of all 7 residues in the sequence with the other 18 natural amino acids identified multiple activity improvements. Those improvements were merged into two optimized leads with 3.2 and 6.9 nM affinities. This proved to be sufficient for application in a diagnostic kit for monitoring antibody levels in patient sera.

Read more about this case here

Case 2: Novel Therapies for HIV/AIDS

Pepscan’s microarray platform technology made it possible to optimize the lead peptide trunc-T2635’s antiviral activity from ~50 nM to ~50 pM. Optimization of multiple amino acid side chains and slight variations in the type of CLIPS™ scaffold used, along with the anchor cysteine positions in the sequences, resulted in an impressive 1000-fold activity improvement. It yielded optimized peptides displaying prolonged antiviral activities in in vivo mouse experiments after challenge with the real HIV virus.

Case 3: Bicyclic Binder to mAb197 (a-CCR7)

In collaboration with one of our customers, Pepscan discovered a 5×5 lead bicycle peptide (among many other leads) with specific affinity for the anti-CCR7 monoclonal antibody mAb197. Stepwise optimization via multiple iterative cycles resulted in affinity improvement of ~200-fold from 60 nM (lead peptide) to 310 pM for the fully optimized lead. 50% of the amino acid mutations leading to this affinity improvement involved introduction of the non-natural amino acids L-norleucine and L-aminobutyric in the core of the epitope. These compounds were of great help during the development of Pepscan’s therapeutic anti-CCR7 mAb CAP100 that is currently in a phase Ia clinical trial in the US.

Case 4: Plasminogen-Activator Inhibitor (UK18)

Attempts to optimize this inhibitor using computational simulations had largely failed (CBC 2013). Pepscan’s microarrays identified 4 different amino acid replacements showing decent improvement of both binding and inhibition of μPA. When combined, these 4 mutations together improved the IC50 from 68 to 35 nM. Despite the relatively small improvements in activity, the lead optimization created significant value for the customer.

Read more about this case in these studies:
1. Angelini A et al, ACS Chem. Biol. 2012, 7:817-21
2. Chen S et al, ChemBioChem 2013, 14:1316-22

Pepscan builds on a distinctive 25-year track record of advances at the frontlines of peptide science. Our highly skilled project teams combine expertise in chemistry and biology – well-equipped to improve the affinity of your candidate peptide drug.

Interested in learning how we can support your specific peptide case? Feel free to reach out to Peter Timmerman, Chief Scientific Officer at Pepscan.

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