Conjugation and Labeling of Molecules: A Burgeoning Approach in Therapeutics Development and Molecular Imaging

Conjugation is the process of formation of a single, stable hybrid, wherein one of the entities is a molecule, such as protein, antibody, peptide and small molecule. These molecules can be conjugated with various modalities, such as haptens, enzymes, isotopes, fluorescent tags, carrier proteins, polymers, particle conjugates and photoreactive molecules. Bioconjugation is a subset of conjugation where one of the entity is a biomolecule, such as protein or an antibody. Bioconjugation is being widely adopted to devise complex structures having the ability to retain the properties and functions intrinsic to individual entities. A typical bioconjugate comprise of three main components, namely target molecules (peptides, proteins, oligonucleotides and lipids), chemical linkers and therapeutic agents (small molecules and macromolecules). The synergistic behavior achieved from the process circumvents the inherent limitation of the individual counterparts, such as short in vivo half-life, low solubility and immunogenicity. Bioconjugation enhances molecular stability, shields the conjugated biomolecules from proteolysis, and improve the targeting properties of the delivery systems.

The concept of bioconjugation dates back to the 1970s, when bovine serum albumin (BSA) was conjugated to polyethylene glycol (PEG) in order to investigate the reduction in immunogenicity. Lately, with the advent in chemical conjugation strategies and bioengineering approaches, substantial progress has been made in order to achieve stable, homogenous and site-specific bioconjugates. It is worth mentioning that the first radiopharmaceutical peptide-drug conjugate Luthathera was approved by United States Food and Drug Administration (USFDA) in 2018 for the treatment of gastroenteropancreatic neuroendocrine tumors. It consists of somatostatin-derived peptide and DOTA complexed with radioactive isotope 77Lu.

Advantages of Conjugated and Labeled Biomolecules

The conjugation of biomolecules is also referred to as biomolecule labeling when the modification with conjugates lead to detection (direct / indirect) for bioimaging and immunoassays. Several conjugates which can confer the detection of labeled biomolecule include fluorescent tags / fluorophores, reporter enzymes (horseradish peroxidase (HRP) and alkaline phosphatase (AP)), biotin, nanoparticles, quantum dots and isotopes. These conjugates lead to elucidation of complex biological processes via signal amplification and high biological specificity. It is worth noting that bioconjugation with stable (non-radioactive) isotopes is widely employed for the analysis of dynamics and metabolism of small molecules. Moreover, it provides a better understanding of the disposition of the drug and its role in causing organ toxicity. Over time, bioconjugation and labeling has become an indispensable tool in the domain of biotechnology and modern chemical biology to improve the biological performance of biomolecules.

Conjugation with a Variety of Molecular Conjugates and Labels

The combination of the conjugates / labels with molecules (proteins, peptides, antibodies and small molecules) is being used abundantly for several applications, ranging from therapeutics and diagnostics to isolation and characterization of drug delivery systems. Conjugates, such as enzymes, streptavidin, magnetic beads and photoluminescent quantum dots are complexed with biomolecules in order to support the robust and sensitive detection of the disease-causing agents. Further, small molecules are conjugated with carrier protein to confirm the production of antibody via ELISA screening. Fluorophores are another class of labels used for screening, these entities are beneficial to explore the novel pharmacophores for ligands specific to markers expressed in cancer cells. The below figure highlights the different types of molecular conjugates and labels that can be conjugated with various molecules.

Types of Molecular Conjugates and Labels

What are the Applications of Conjugated and Labeled Biomolecules?

The combination of conjugates / labels with molecules is being used abundantly for several applications, ranging from therapeutics and diagnostics to isolation and characterization of drug delivery systems. Conjugated biomolecules are extensively used for screening purposes and have been adopted in techniques, such as immunochemical staining, fluorescence microscopy and high content analysis (HCA). To obtain the high-throughput screening of potential ligands, small molecules act as conjugates to bind with the biomolecules and function as probe upon binding to ligand. Enzymes, streptavidin, magnetic beads and photoluminescent quantum dots, when complexed with biomolecules, support the robust and sensitive detection of disease-causing agents. Further, bioconjugation with probes (gold nanoparticles) is carried out for formation of biosensors to detect multiple analytes. Moreover, polymers, sugars, carrier proteins, lipid-conjugated peptides display the potential to act as peptide therapeutics for various diseases. Moreover, the carrier protein-peptide complex facilitates the production of antibodies against peptides. It is worth mentioning that high specificity, programmability and biocompatibility of proteins renders its role as drug carriers. Nonetheless, functionalization of these biomolecules is necessary to enhance the delivery capability, which can be limited due to cell-membrane impermeability, rapid clearance and poor pharmacokinetics. Conjugates, such as polymers and cell penetrating peptides, have been significantly used in the delivery of these therapeutic agents, without compromising its therapeutic effect.

The advancements in conjugation and labeling of biomolecules has facilitated the study of molecular structures and interactions that finds applicability in a number of cutting-edge areas, such as drug discovery, detection, biosensing and imaging. Also, the conjugates have the potential to act as nanotheranostic agents post fabrication in the nanoparticles, thereby, offering several advantages, such as sustained and controlled delivery, increased solubility and drug safety. Further, there is increased focus on developing simple bioconjugates that can serve the purpose of modification, wherein the molecules are expected to be highly stable, selective and provide the desired functionalization. However, novel conjugates / labels are now being engineered to strengthen the properties of the resultant bioconjugates. Conjugation of two anti-tumor agents, such as bispecific aptamers and antibodies, is one such novel method that has the potential to improve therapeutic efficacy and specificity in killing the tumor.

What are the Benefits of Outsourcing Conjugation and Labeling Operations to Service Providers?

One of the critical factors associated with the development of conjugated and labeled molecules is the expertise of click-chemistry and availability of reliable, advanced conjugation technology to carry out the process. In addition, formation of the homogenous bioconjugates is a complex process, especially if there is the presence of molecules having similar functional groups.

Benefits of Outsourcing Conjugation and Labeling Operations

Owing to the advanced bioconjugation technologies, technical and scale-up challenges associated with these conjugated entities, the reliability on stakeholders having the expertise in this domain has upsurged. Additionally, given that conjugated biomolecules have demonstrated some clinical promise for various therapeutic areas, the stakeholders are leveraging expertise of service providers offering conjugation and labeling services. These service providers are actively upgrading their chemistry and biological capabilities to accommodate the demand for such products. This will eventually bypass the associated key translational challenges, including good manufacturing practice (GMP) standards, regulatory compliance and quality related issues. Driven by the growing research efforts, development of different conjugated / labeled biomolecules, and efforts of various stakeholders, this segment of the industry is likely to witness noteworthy growth in the foreseen future.

Bottom Line

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