A Review of Protein- and Peptide-Based Chemical Conjugates: Past, Present, and Future

Abstract

Over the past few decades, the complexity of molecular entities being advanced for therapeutic purposes has continued to evolve. A main propellent fueling innovation is the perpetual mandate within the pharmaceutical industry to meet the needs of novel disease areas and/or delivery challenges. As new mechanisms of action are uncovered, and as our understanding of existing mechanisms grows, the properties that are required and/or leveraged to enable therapeutic development continue to expand. One rapidly evolving area of interest is that of chemically enhanced peptide and protein therapeutics. While a variety of conjugate molecules such as antibody–drug conjugates, peptide/protein–PEG conjugates, and protein conjugate vaccines are already well established, others, such as antibody–oligonucleotide conjugates and peptide/protein conjugates using non-PEG polymers, are newer to clinical development. This review will evaluate the current development landscape of protein-based chemical conjugates with special attention to considerations such as modulation of pharmacokinetics, safety/tolerability, and entry into difficult to access targets, as well as bioavailability. Furthermore, for the purpose of this review, the types of molecules discussed are divided into two categories: (1) therapeutics that are enhanced by protein or peptide bioconjugation, and (2) protein and peptide therapeutics that require chemical modifications. Overall, the breadth of novel peptide- or protein-based therapeutics moving through the pipeline each year supports a path forward for the pursuit of even more complex therapeutic strategies.

Site-selective post-modification of short α/γ hybrid foldamers: a powerful approach for molecular diversification towards biomedical applications

“…The late-stage modification approach is successfully employed in peptides, 25 proteins, 26 and polymers 27 for the desired applications. It is challenging to achieve post-functionalization of a molecule having two identical reacting sites with two different functional groups (regioselective functionalization).…”

Diligent Design Enables Antibody-ASO Conjugates with Optimal Pharmacokinetic Properties

“…Although ASOs constitute a different payload class with distinct properties, such as negative charge and higher molecular weight, as compared to classical cytotoxins, 18 some learnings from the decades-long development path of ADCs can be transferred to the design of antibody-oligonucleotide conjugates. 19 The ADC field has shown that a diligent conjugate design, including choice of drug-to-antibody ratio (DAR), linker, conjugation site, and conjugation technology, is of high importance to creating CMC (Chemistry, Manufacturing and Controls)-fit drug candidates quickly and to improving the chances for clinical success. 20 The first generation of FDA-approved ADCs was produced with chemical conjugation methods (e.g., using reduced disulfides or lysines).…”

Chemically Enhanced Peptide and Protein Therapeutics

“…This Special Issue contains several publications showing a wide variety of strategies to enhance peptide activity. As Shatz-Binder and collaborators describe [ 3 ], in order to decrease blood clearance, therapeutic peptides may be conjugated to polymers or proteins such as albumin, antibody crystallizable fragments (Fc), or nanoparticles. Increasing peptide residence time and their accessibility for immune recognition is key in peptide vaccines.…”

“…In proteins, the most extended modification is PEGylation, which reduces protein aggregation, immune recognition, protease degradation, and renal clearance [ 3 ]. Chemical enhancement has also been used to boost protein function, such as increasing enzyme activity with non-canonical amino acids [ 19 ], improving thermal stability in proteomimetics [ 20 ], and generating targeted conjugates.…”

“…ADCs couple the high selectivity of the antibody to the high potency of the antineoplastic toxin. An update on the current trends of this class of chemically enhanced antibodies is also presented in the review by Shatz-Binder and collaborators [ 3 ]. A key parameter in the development of ADCs is the linker between the antibody and the cytotoxic agent, as its characteristics impact the efficacy and pharmacokinetics of the drug.…”