Protein-polymer conjugates are widely used as disease therapeutics and have advantages such as high target specificity. but their use also faces some challenges: rapid clearance and low physical stability.
Current FDA-approved protein conjugates are all covalently linked to poly (ethylene glycol) (PEG). These PEGylated drugs have a longer half-life in the blood and less frequent dosing, which is a significant advantage for patients. However, PEG has some potential disadvantages that require the development of alternatives, so the development of polymers with enhanced pharmacokinetic properties, as well as other advantages such as improved stability or degradability, is important to advance the field of protein therapeutics.
Since the first recombinant insulin was approved in 1984, recombinant protein drugs have gradually been favored by people because of their high specificity and high activity;
In recent years, the number of protein drug approvals has faintly surpassed that of traditional small molecule drugs. However, protein drugs often have poor pharmacokinetics, short cycle time, and high-frequency repeated medication, which brings great inconvenience and economic burden to patients.
Another more serious problem is the high immunogenicity of protein drugs. Taking all kinds of recombinant antibodies as an example, even fully humanized antibodies will produce a large number of anti-drug antibodies (anti-drug antibodies, referred to as ADA) after multiple injections; In severe cases, it can cause severe allergic reactions and even threaten the lives of patients.
Therefore, how to avoid the production of ADA in the process of clinical drug use (especially in the process of multiple drug administration) has become a necessary prerequisite for the development of protein drugs. Protein PEGylation can not only prolong the protein circulation time, but also reduce the immunogenicity of the protein to a certain extent through its own steric hindrance effect.
However, PEG itself induces the immune system to produce anti-PEG antibodies (essentially a kind of ADA), which in turn leads to accelerated blood clearance (abbreviated as the ABC effect). In summary, it is urgent to find new polymers with low immunogenicity for protein modification to simultaneously achieve long circulation and inhibit ADA production.
Polyamino acid (also known as synthetic polypeptide) is a synthetic polymer that mimics the structure of protein polypeptides. It is biodegradable and has low biological toxicity. It is an ideal protein drug modification polymer.
Protein-polymer conjugates play a pivotal role in disease therapeutics due to their high specificity and low off-target, but proteins are rapidly cleared or inactivated in the body through metabolism, excretion and other pathways, enhancing protein properties (e.g. pharmacokinetics) There are two main approaches: one is the use of recombinant DNA techniques to replace amino acids or create fusion proteins; the other is conjugates of synthetic polymers, the most common example of which is polyethylene glycol (PEG) .
However, synthesizing protein-polymer conjugates is not always straightforward and multiple factors need to be considered: choice of polymer, choice of protein target, choice of conjugation chemistry, and in vitro and in vivo characterization of the conjugation.
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– Protein-drug Conjugation
– Fluorophore Conjugation
– Biotin conjugation
– Antibody-drug conjugate (ADC)
– Polymer–drug conjugation
– Polymer-drug-target ligand conjugation
– Cysteine-based conjugation
– Lysine-based conjugation
– Thio-engineered antibody
– Carbohydrate-based conjugation
– Unnatural amino acids-based conjugation