Week 1, September 2026: Engineering Peptides into Antibodies: Recent Directions in Therapeutic Design

Peptides and antibodies have different strengths as therapeutic molecules. Peptides are short chains of amino acids that can bind compact or structurally difficult targets, while monoclonal antibodies offer high specificity, long circulation times and, depending on their format, immune effector functions. A recent review from researchers at the Technical University of Munich has explored ways to combine these properties by incorporating functional peptides into antibodies or antibody fragments. The resulting constructs are being studied for multispecific targeting, conditional activation, altered biodistribution, intracellular delivery, and improved peptide pharmacokinetics.

Peptides as Part of the Antibody Binding Surface

One approach is peptide grafting, in which a peptide sequence is inserted into an exposed loop of an antibody. Many studies have focused on the complementarity-determining regions (CDRs), the loops within the antibody variable domains that make up much of the antigen-binding surface. CDR-H3 is frequently used because it naturally tolerates considerable sequence and structural diversity, although other CDRs and framework loops can also accommodate peptide sequences.

Research is also extending grafting to more structurally constrained peptides. Disulfide-rich peptides, which are stabilized by bonds between cysteine residues, can form small binding surfaces capable of recognizing recessed or concave epitopes. Bovine antibodies provide a natural example: some contain unusually long CDR-H3 regions ending in disulfide-rich “knob” domains, which have subsequently been adapted for experimental bispecific antibody designs.

Meanwhile, macrocyclic peptides are in ring-like structures that can stabilize a particular binding conformation. Methods such as lasso-grafting transfer macrocyclic peptide binding sequences into exposed protein loops, allowing the antibody scaffold to help preserve their geometry. Experimental studies have used this strategy to generate molecules with multiple binding specificities and altered pharmacokinetic properties.

Adding Peptides to Antibodies

Peptides can also be genetically fused to the N- or C-terminus of an antibody heavy or light chain. This format is comparatively modular and has been used to add binding sites, alter tissue distribution, or improve cellular uptake.

For example, peptide recognition domains have been added to antibodies to create bispecific or multispecific molecules, meaning that a single construct can recognize two or more molecular targets. Experimental systems have combined the original antibody specificity with additional peptide-based recognition domains.

Researchers have also investigated cell-penetrating peptides, which are short sequences that can promote cellular uptake, as a way to deliver antibodies inside cells. However, results depend strongly on the peptide sequence and fusion site.

Conditional Antibody Activity

Peptides can also be used as temporary masks that restrict antibody activity.

In these designs, a masking peptide blocks antigen binding until a protease, an enzyme that cuts proteins, removes the mask through a cleavable linker. The aim is to concentrate antibody activity in tissues where the relevant protease is present.

Antibodies as Carriers for Therapeutic Peptides

The relationship can also work in the opposite direction: instead of adding a peptide to improve an antibody, an antibody-derived scaffold can improve the properties of a therapeutic peptide.

The Fc region is the constant portion of an antibody involved in immune interactions and FcRn-mediated recycling, which contributes to the long circulating half-life of IgG antibodies. Fusing therapeutic peptides to Fc can extend their time in circulation.

There are several approved Fc-peptide therapeutics, such as romiplostim, dulaglutide, and efsubaglutide alfa.

Developability Still Sets the Boundaries

Developability refers to whether a therapeutic molecule can be produced, formulated, and stored with stability and consistency.

Antibody-peptide constructs can show poor expression, peptide clipping, aggregation, heterogeneous conjugation, or loss of structural stability. Immunogenicity could also occur if both the peptide itself and newly created peptide-linker junctions are recognized by the immune system.

Computational protein-design methods are increasingly being used to guide these choices, but experimental characterization, such as with RushData, remains necessary.