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.

Keywords: ADC; AOC; antibody delivery; bioconjugation; protein conjugate vaccines; protein delivery; protein therapeutics; protein–polymer conjugates.

Figure 1

ADCs are made up of the antibody (blue), the payload (red), and the chemical conjugation (green) that brings them together. Functions and the most critical design considerations for each component have been listed. Created with BioRender.com.

Figure 2

Routes of administration that have been used for (A) oligonucleotides and AOC delivery in the clinic and (B) for preclinical AOC delivery (IP: intraperitoneal, IM: intramuscular, IV: intravenous, IT: intrathecal, ITV: intravitreal, SC: subcutaneous). Created with BioRender.com.

Figure 3

Schematic representation of protein conjugate vaccine approaches, demonstrating differences in geometry and valency in chemical conjugations, site-specific approaches, and VLPs, including (A) nonspecific chemical coupling, (B) bioconjugation, (C) click chemistry via non-native amino acids, (D) noncovalent modification using biotin and streptavidin, and (E) coupling to virus-like particles (VLPs). Created with BioRender.com.

Figure 4

Overview of polymer (A) chemical structures and (B) architectures discussed in this section.

Figure 5

The diversifying applications of polymer–protein and polymer–peptide conjugates. While conventional conjugates were developed to improve the systemic half-life of peptides and proteins, recent work has demonstrated the ability of polymer conjugates to extend intravitreal half-life, alter the specificity of the conjugated protein, facilitate multivalent display of the API, improve the properties of ADCs, and enable the production of prodrug–polymer conjugates. Created with BioRender.com.

Figure 6

Example PK profiles for an unmodified protein, polymer conjugate with extended systemic half-life, and a prodrug–polymer conjugation that undergoes gradual activation in circulation. First-order clearance is assumed for simplicity.