This work discusses peptide grafting into hypervariable and framework loops, terminal fusion to antibody chains, Fc-peptide fusion proteins, and bioconjugation approaches, and examines examples that illustrate the importance of insertion site, peptide topology, and linker design for folding, activity, and developability.
Abstract
Peptides and antibodies occupy complementary therapeutic niches. Peptides offer compact size and high-affinity recognition of difficult targets, whereas antibodies provide exquisite specificity, long serum half-life, and effector functions. Here we review strategies that merge these modalities by engineering peptides into immunoglobulins and antibody fragments. We discuss peptide grafting into hypervariable and framework loops, terminal fusion to antibody chains, Fc-peptide fusion proteins, and bioconjugation approaches. Across these formats, we examine examples that illustrate the importance of insertion site, peptide topology, and linker design for folding, activity, and developability. We highlight how antibody fusion and conjugation with natural and engineered peptides can confer novel target binding, conditional activation, altered biodistribution, improved pharmacokinetics, or intracellular delivery, and we discuss how disulfide-rich and macrocyclic peptides have enriched the design space. Finally, we also point out key translational challenges, including manufacturability, stability, heterogeneity, and immunogenicity, and propose that advances in protein design and chemical bioconjugation will enable next-generation therapeutics at the interface of antibodies and peptides.
Antibody-oligonucleotide conjugates (AOCs) have emerged as a promising therapeutic platform that integrates the targeting capability of antibodies with the gene-regulatory potential of oligonucleotide payloads. By enabling cell or tissue selective delivery, AOCs may extend oligonucleotide therapeutics beyond liver predominant distribution and broaden intervention strategies for intracellular targets that have historically been difficult to drug. However, their therapeutic performance is not determined by target binding alone, but also by productive intracellular delivery, including receptor mediated uptake, endosomal trafficking, payload release, and functional access to cytoplasmic or nuclear compartments. In this review, we summarize the key design principles governing AOCs performance, including target biology, antibody formats, oligonucleotide payload classes, chemical modifications, linker design, conjugation strategies, and critical quality attributes. We further discuss the intracellular fate of AOCs and highlight endosomal escape as a major rate limiting step that often constrains biological activity despite efficient cellular uptake. In addition, we review current translational progress, with particular emphasis on neuromuscular disorders, as well as emerging applications in oncology, central nervous system diseases, and other indications. Finally, we outline major challenges and future directions that are likely to shape the next generation of AOCs therapeutics.
Yuqian Li, Xinlin Liu, Fuyuan Zhang et al.· Journal of Hematology & Onco...· 0 citations
Peptide-based therapeutics have become a flexible type of medicine that combines high target specificity and strong biological activity with good safety profiles. They effectively connect small-molecule drugs and biologics. Since insulin was first used in 1922, more than 100 peptide drugs have been approved around the world, and their use is growing in diabetes, cancer, rare diseases, and autoimmune disorders. However, their clinical use is still limited by rapid enzymatic degradation, short half-life, poor membrane permeability, low oral bioavailability, and formulation instability. This review presents a unified innovation framework that integrates upstream molecular engineering strategies including cyclization, peptide stapling, D- and β-amino acid substitution, PEGylation, and backbone modification with downstream advanced delivery platforms such as nanocarriers, microneedles, self-assembling hydrogels, and stimuli-responsive systems, while also addressing critical translational considerations including scalability, regulatory requirements, and manufacturing consistency. By critically linking structural modifications at the molecular level with formulation performance and clinical translation factors, and by evaluating both approved products and persistent gaps in predictive modelling and patient-centric delivery, this work offers practical insights that go beyond the scope of most existing reviews. The integrated perspective presented here highlights how these combined approaches are shifting peptide therapeutics from conventional injectable formats toward more stable, convenient, and precisely targeted solutions, paving the way for the next generation of patient-friendly peptide medicines.
Pradip Karale, Saloni Borse, Anjali Gavit et al.· Journal of Pharmaceutical In...· 0 citations
Oligonucleotide therapeutics represent an expanding class of medicines that can regulate gene expression, RNA processing, protein translation, immune signaling, and biomolecular recognition through sequence-specific or structure-dependent mechanisms. Despite clinical progress, their application remains constrained by nuclease degradation, rapid clearance, inefficient tissue and cellular delivery, endosomal sequestration, off-target activity, immune recognition, and mechanism-specific requirements for target engagement. Chemical modification is central to oligonucleotide therapeutic development because it can mitigate some of these limitations while influencing target affinity, protein binding, pharmacokinetics, and intracellular activity. This review examines chemical modification strategies to improve the biological stability and functional performance of therapeutic oligonucleotides and is organized around major classes of chemical modification, including phosphate and backbone-linkage modifications, sugar and conformational modifications, backbone-replacement analogs, and conjugation-based approaches. Rather than presenting these chemistries as uniformly beneficial, this review emphasizes that the same modification can be enabling in one therapeutic mechanism and disruptive in another, so its value cannot be judged apart from the modality and molecular architecture in which it is placed. Clinically successful oligonucleotide designs are likely to rely on combinations of chemical features, including modified backbones, modified sugars, stereochemical control, terminal stabilization, and ligand- or formulation-based delivery strategies. Understanding how these features interact is essential to develop more predictable and mechanism-appropriate oligonucleotide therapeutics.
K. Burton, Kristen Dellinger· Molecules· 0 citations
Bispecific antibodies (BsAbs) represent a transformative class of next-generation biologics, enabling simultaneous binding to two targets and offering mechanisms of action beyond conventional monoclonal antibodies. Their growing clinical success, particularly in T-cell–redirecting therapies, has increased the need for robust formulation and Chemistry, Manufacturing, and Controls (CMC) strategies to support complex molecular designs, high potency, and multiple delivery routes. However, BsAbs present unique challenges due to structural heterogeneity, asymmetric domain interfaces, aggregation propensity, and sensitivity to physical and chemical stresses. This review provides a structured overview of formulation strategies for BsAbs, integrating molecular design considerations, developability assessment, and Quality by Design (QbD) principles. It highlights the impact of domain architecture on conformational and colloidal stability and outlines rational selection of excipients including buffers, sugars, amino acids, and surfactants based on (Fragment crystallizable) Fc-containing versus fragment based formats. Key challenges in high-concentration formulations for subcutaneous delivery, such as viscosity control and device compatibility, are also discussed. Critical degradation pathways, including oxidation, chain mispairing, and interfacial stress, are addressed with practical mitigation strategies. The review further describes analytical and stability study approaches to monitor critical quality attributes such as arm specific activity, heterodimer integrity, and stress-induced degradation. Emerging tools, including machine learning and predictive modeling, are also considered to enhance formulation development. Case study understandings identify common risks, including arm-specific potency loss, interface-driven aggregation, and high-viscosity limitations. Overall, this review presents a unified framework to guide the development of stable, manufacturable, and clinically reliable BsAb therapeutics.
Unknown authors· Bulletin of Faculty of Pharm...· 0 citations
ABSTRACT Targeted chimeras have reshaped therapeutic design by converting target recognition into active degradation. As one of the most clinically established therapeutic modalities, antibodies provide high affinity and specificity to the protein of interest. Antibody‐associated targeted chimeras (AbTACs) are emerging as an important class of biologic degraders for targeted protein elimination, particularly of extracellular and membrane‐associated proteins. AbTACs offer a strategy to extend its recognition capacity beyond target binding by coupling defined degradation pathway. In these systems, antibody‐derived binders serve as programmable recognition modules, while conjugated ligands, encoded domains, recruited receptors, or nanoparticle scaffolds determine the target's intracellular fate. This review discusses the conceptual evolution of AbTACs and classifies current platforms according to scaffold architecture and engineering strategies, which link target binding to intracellular routing and subsequent clearance. Furthermore, it highlights the design principles and translational barriers that will guide the development of next‐generation antibody‐associated degraders.
Kaige Chen, Quanyin Hu· Advancement of science· 0 citations
BACKGROUND AND PURPOSE
Site-specific antibody modification is a useful chemical strategy to elaborate antibody therapeutic function. Conventional lysine- or cysteine-based conjugation methods generate heterogeneous products, while protein engineering approaches are resource-intensive. Affinity-guided covalent strategies using antibody binding peptides offer a chemical alternative for selective antibody functionalisation but are limited by challenges with incorporating reactive electrophiles into complex peptide ligands.
EXPERIMENTAL APPROACH
We developed covalent peptide engagers (CPEs) that equip antibodies with new tumour-targeting function. CPEs integrate an Fc-binding peptide, SuFEx electrophile and a target-engager moiety. CPEs were synthesised and evaluated in covalent labelling kinetics and selectivity assays using SDS-PAGE gels and biolayer interferometry (BLI). Functional activity was evaluated using tumour cell-immune cell co-culture assays.
KEY RESULTS
A first-in-class CPE was synthesised incorporating a latent protein-reactive electrophile within a complex Fc-binding peptide. CPEs demonstrate sufficient selectivity/kinetics for site-selective antibody modifications. We observed SuFEx peptide ligand compatibility is dependent on the presence of internal tyrosine or histidine residues, which can inactivate the covalent peptide and/or enhance hydrolysis rate. Anti-tumour function of IgG-CPE was validated by antibody-dependent cellular phagocytosis, demonstrating robust phagocytosis of urokinase-type plasminogen activator receptor (uPAR)-expressing tumour cells. Herceptin functionalised with uPAR-CPE enabled dual-antigen-targeting via phagocytosis of cells co-expressing HER2 and uPAR, consistent with avidity effects associated with engagement of two tumour antigens.
CONCLUSIONS AND IMPLICATIONS
CPEs enable covalent reprogramming of endogenous IgG and monoclonal antibodies, offering an alternative to protein engineering for the rapid generation of multi-specific antibodies and therapeutic engagement of humoral immunity across cancer and infectious disease.
Karolina Krygier, Sandra Szu‐Wei Hwang, A. Rullo· British Journal of Pharmacol...· 0 citations
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