Bio-conjugates: A Growing Class of Biopharmaceuticals

The story of bioconjugates started with a desire to improve the functionality of a biomolecule used in basic research, drug delivery, diagnostic or medical devices. It plays inseparable role in designing & delivery of biomolecule hence it is of great importance in the field of drug development process. Currently bioconjugates are most widely used in delivering oligonucleotides to specific cells and organs.   

Bioconjugates involves the science of polymer chemistry, macromolecules & biomolecules. The precise number of bioconjugates that exist is impossible to pinpoint because of the dynamic nature of bioconjugate research and the enormous number of possible combinations. Bioconjugates can been exploited for used in drug development or research based on the type of biomolecule, type of conjugate chemistry & application in medical use. The foundation of bioconjugation is a logical and intelligible molecular design. In isolation, the constituent molecules of a bioconjugate have undergone extensive characterization and have undergone rigorous laboratory testing. Nevertheless, the bioconjugated molecule has unique characteristics once they are combined. [1] 

When looked at the type of biomolecule it could be any of the following:   

1) Protein-polymer conjugates (PPCs) which are in general protein linked to the synthetic polymer e.g. polyethylene glycol (PEG);   

2) Antibody drug conjugates (ADCs) which are antibody linked to the potent drug molecule allowing targeted delivery e.g. Kadcyla (trastuzumab emtansine) is a drug approved by the US Food and Drug Administration (FDA) for the treatment of specific types of HER2-positive breast cancer; 

3) Nucleic acid conjugates which involve biomolecules as oligonucleotides (DNA, RNA, CRISPER-cas, siRNA etc.) linked to other molecules generally polymers for developing gene therapies or diagnostics;   

4) Carbohydrate conjugates involves attaching carbohydrates to other molecules for improving solubility & targeting the specific cell type. 

There are notable companies that offer PPCs or related products and services such as Merck KGaA that offers various bioconjugation products and services, including custom PPC synthesis; it's subsidiary Sigma-Aldrich that offers pre-made PPCs and building blocks for PPC synthesis; Creative PEG Works a company specializing in PEGylation (polyethylene glycol conjugation) services, which is a common type of PPC technology ; ProMab Biotechnologies, Inc. providing contract research and manufacturing services for bioconjugates, including PPCs; Adimab LLC a company focused on the discovery and development of fully human antibodies, some of which involve PPC technologies while there are many other companies offering the service and the list is exhaustive. Similarly there are notable companies that offer ADC related products such as Seattle Genetics, Inc. that offers a comprehensive range of ADC development services, including conjugation chemistry, linker and payload development, and manufacturing capabilities; Contract Research Organizations (CROs) like WuXi AppTec , Catalent , and Charles River Laboratories offer a variety of ADC development services, including conjugation, analytical development, and manufacturing support; then ADC based companies e.g. ADC Therapeutics , Roche , and Seagen Inc. also offer ADC development services, often focused on specific ADC platforms or technologies they have developed. Cytiva, formerly GE Healthcare Life Sciences, offers a variety of bioconjugation products and services, including those related to antibody-drug conjugates (ADCs).[2] 

There are companies that are making nucleic acid-based conjugates namely TriLink Biotech that offers custom conjugation services; Icos Pharmaceuticals a subsidiary of Eli Lilly and Company that utilize its in-house nucleic acid conjugates to develops and commercializes pharmaceuticals for various therapeutic areas; Mirna Therapeutics is a company focuses on developing microRNA therapeutics, which are a type of nucleic acid-based therapy; Roche Diagnostics offers a variety of diagnostic products that utilizes nucleic acid conjugates and similarly is Asuragen a company that develops and manufactures genetic testing products, some of which involve nucleic acid conjugates.[3] 

New in the race is Liberate Bio is a privately held biotechnology company founded in 2022 and headquartered in Boston, Massachusetts. They focus on developing novel delivery vehicles for oligonucleotide therapeutics. Their mission is to enable precise delivery of DNA, RNA, or other cargo to disease-relevant tissues and unlock the full potential of genetic medicines. This company uses machine learning, advanced chemistry, and molecular biology techniques to identify and develop new lipid nanoparticle (LNP) delivery vehicles. Unlike many other LNP companies targeting liver delivery, Liberate Bio aims to advance non-viral delivery technologies beyond the liver for disease-relevant tissues.[4] 

Ranging from drug delivery to diagnostics, several companies are working on carbohydrate conjugates such as GlycoMimetics Danish biotechnology company having a lead product, rivirixumab, is a carbohydrate conjugate in clinical trials for treating respiratory syncytial virus (RSV) infection and the company is focuses on developing carbohydrate-based drugs and diagnostics; X-Chem Therapeutics Massachusetts-based company utilizes computational methods to design and develop carbohydrate-based drugs and currently exploring their carbohydrate conjugates for various applications, including cancer and inflammatory diseases; Lectera is a French company specializes in developing carbohydrate-based vaccines and immunotherapies; Incanthera is also a French company focuses on developing carbohydrate-based vaccines and therapeutic agents; Creative Biolabs is a contract research organization offers custom services for developing and manufacturing bioconjugates, including those involving carbohydrates and they also provide expertise in various conjugation chemistries and have experience working with diverse carbohydrate moieties.[5] 

Linkers are unique components that connect bioconjugated units, these could be cleavable or non-cleavable and joins a functional (bio) molecule to molecular tag in order to create a conjugate of interest. Action of enzymes and the particular acidic media inside the cells, for instance, are capable of breaking linker. Payload is a functional molecule that is joined to a biomolecule such as a protein or antibody via linker. Payload unlike a molecular tag, are hybrid and complex molecules with special qualities and functions. These are synthetic or semi synthetic in nature, e.g. Trastuzumab Emtansine (Kadcyla®) approved in Her2 positive breast cancer treatment utilizes a payload that is based on the potent microtubule disrupting agent Emtansine, which is derived from the natural product maytansine, a semi-synthetic compound. Likewise, Auristatins are potent microtubule disrupting agents that are pentapeptides with being highly modular and can be attached to antibodies using all types of linkers and linking strategies. These synthetic analouges are based off the natural product dolastatin 10 and are currently being used in the marketed ADCs Brentuximab Vedotin (Adcetris®), Enfortumab Vedotin (Padcev®), and Polatuzumab Vedotin (Polivy®).[6] 

Based on the chemistry or method of synthesis of the conjugates, these can be of various types such as 1) Click Chemistry which is a method utilizes specific functional groups to form rapid and reliable linkages between molecules e.g. NOTA-conjugated antibodies (NOTA) are labeled with a chelator molecule (NOTA) using click chemistry for radioisotope conjugation, allowing for PET imaging of specific targets in the body, like wise Trastuzumab Emtansine (Kadcyla®) is also uses a click reaction (Azide-Alkyne cycloaddition) to link the antibody trastuzumab to the cytotoxic drug emtansine; 2) Staudinger Ligation technique utilizes specific phosphine and azide groups to form bioconjugates carbohydrates to proteins, drugs with antibodies or desired amino acid derivative; 3) Thiol-Ene Reaction is an approach that involves coupling thiol and alkene groups for bioconjugation and are frequently used to conjugate polymers with cysteine residues on proteins, creating PPCs with various applications such as drug delivery and creating biosensors or scaffolds for tissue engineering; 4) Enzyme-Mediated Conjugation method utilizes enzymes to facilitate the formation of specific linkages between molecules. Unlike above discussed conjygate chemistry it utilizes the catalytic properties of enzymes to selectively link two molecules together, offering several advantages over traditional chemical conjugation methods e.g Sortase, Transglutaminase and Formylglycine Generating Enzyme (FGE). [7] 

In conclusion, bioconjugates play a crucial role in delivering biomolecules like drugs and oligonucleotides to specific targets in the body. The field of bioconjugate research is dynamic and diverse, with numerous types of bioconjugates and applications constantly evolving. Several companies are actively developing and offering bioconjugates and related services for various therapeutic and diagnostic purposes. Certainly there is a growing importance of bioconjugates in various fields, particularly drug development and delivery. 

References: 

1. Mohs RC, Greig NH. Drug discovery and development: Role of basic biological research. Alzheimers Dement (N Y). 2017 Nov 11;3(4):651-657. doi: 10.1016/j.trci.2017.10.005. PMID: 29255791; PMCID: PMC5725284.

2. Angus Liu, Feirce Pharma Published date Aug 9, 2021; accessed date Mar 2024. URL: https://www.fiercepharma.com/pharma/taking-aim-at-roche-and-astra-daiichi-seagen-bets up-to-2-6b-china-s-first-home-made-adc.

3. Leung D, Wurst JM, Liu T, Martinez RM, Datta-Mannan A, Feng Y. Antibody Conjugates Recent Advances and Future Innovations. Antibodies. 2020; 9(1):2. https://doi.org/10.3390/antib9010002

4. ACS Science Talks: Virtual Lecture Series Mar 4, 2024 19:30 India Talk Title: Macromolecular Nucleic Acid Delivery Vehicles and Bioconjugates via Parallel Experiment and Computation   Speaker: Prof. Theresa M. Reineke Prager Chair in Macromolecular Science and Distinguished McKnight University Professor, Department of Chemistry, University of Minnesota, Minneapolis Editor-in-Chief of Bioconjugate Chemistry.

5. Oyama S, Yamamoto T, Yamayoshi A. Recent Advances in the Delivery Carriers and Chemical Conjugation Strategies for Nucleic Acid Drugs. Cancers (Basel). 2021 Aug 1;13(15):3881. doi: 10.3390/cancers13153881. PMID: 34359781; PMCID: PMC8345803.

6. NJ Bio integrated Chemistry Service Provider website URL: https://njbio.com/payloads linkers-antibody-drug-conjugates/

7. Mushtaq S, Yun SJ, Jeon J. Recent Advances in Bioorthogonal Click Chemistry for Efficient Synthesis of Radiotracers and Radiopharmaceuticals. Molecules. 2019 Oct 2;24(19):3567. doi: 10.3390/molecules24193567. PMID: 31581645; PMCID: PMC6803924.

About the Author:

Shruti Talashi

Ms. Shruti  Talashi  boasts a dual mastery of lab research and writing. Her doctoral study outcome as M.Phil in biomedical science while studying breast cancer and an extraordinary masters degrees dissertation work on exploring role of Gal-lectin in cancer metastasis fuels her extensive research interests. She has gained few publication in journals. Bridging the science-public gap is her passion, aided by expertise in diverse techniques. From oncology to antibiotic/drugs production, she's led and managed complex projects, even clinical trials. Now, as a freelance Content Coordinator for Sinoexpo Pharmasource.com, her industry knowledge shines through valuable insights on cutting-edge topics like GMP, QbD, and biofoundry.