Concordance of preclinical and clinical pharmacology and toxicology of monoclonal antibodies and fusion proteins: soluble targets

Biotherapeutics is a rapidly growing segment of the entire pharmaceutical industry that constitutes approximately one-quarter of ongoing new drug endorsements. Monoclonal antibodies are a major part of these endorsements every year (mAbs). MAbs' non-clinical pharmacology and toxicology research compare with substance components during progression, since these biotherapeutics are extracted from an organic source, and to inspire a pharmacological reaction, the creature models must also have similar epitopes (focuses) as individuals. Biotherapeutic items (BTPs) are the quickest developing drugs in the pharmaceutical market. Despite their clinical achievement, the immunogenicity of BTPs keeps on being a significant concern. The subcutaneous (SC) course is to cultivate a passion for the organisation of biotherapeutics. Both monoclonal antibodies and various biotherapeutics are discussed. Medicine has been disrupted by biotherapeutic drugs (BPs), altering the way we treat a few processes. Comparative BPs (SBPs) are discussed here, also called biosimilars, including the assembly process and administrative viewpoints used. Monoclonal antibodies can apply synergistic antitumour impacts in blend with other immunomodulatory approaches, for example, chemotherapy, radiotherapy, directed treatment specialists, immunisations, or different immunomodulators. Probiotics have gotten profoundly perceived as enhancements for people and specifically for creatures given their gainful result on wellbeing improvement and prosperity support.

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Biotherapeutics: Challenges and Opportunities for Predictive Toxicology of Monoclonal Antibodies

International Journal of Molecular Sciences ◽

10.3390/ijms19113685 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3685 ◽

Cited By ~ 3

Author(s):

Dale Johnson

Keyword(s):

Clinical Pharmacology ◽

Monoclonal Antibodies ◽

Drug Reactions ◽

Predictive Toxicology ◽

Mechanisms Of Toxicity ◽

Biological Source ◽

Pharmacological Response ◽

Challenges And Opportunities ◽

New Methodologies ◽

Pharmacology And Toxicology

Biotherapeutics are a rapidly growing portion of the total pharmaceutical market accounting for almost one-half of recent new drug approvals. A major portion of these approvals each year are monoclonal antibodies (mAbs). During development, non-clinical pharmacology and toxicology testing of mAbs differs from that done with chemical entities since these biotherapeutics are derived from a biological source and therefore the animal models must share the same epitopes (targets) as humans to elicit a pharmacological response. Mechanisms of toxicity of mAbs are both pharmacological and non-pharmacological in nature; however, standard in silico predictive toxicological methods used in research and development of chemical entities currently do not apply to these biotherapeutics. Challenges and potential opportunities exist for new methodologies to provide a more predictive program to assess and monitor potential adverse drug reactions of mAbs for specific patients before and during clinical trials and after market approval.

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Abstracts of the 87th Annual Meeting of the German Society for Experimental and Clinical Pharmacology and Toxicology (DGPT) with contribution of the Arbeitsgemeinschaft für Angewandte Humanpharmakologie e. V. (AGAH)

Naunyn-Schmiedeberg s Archives of Pharmacology ◽

10.1007/s00210-021-02066-6 ◽

2021 ◽

Keyword(s):

Clinical Pharmacology ◽

Annual Meeting ◽

German Society ◽

Pharmacology And Toxicology

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Use of recombinant fusion proteins for generation and rapid characterization of monoclonal antibodies

Journal of Immunological Methods ◽

10.1016/s0022-1759(12)80022-6 ◽

1992 ◽

Vol 147 (1) ◽

pp. 1-11 ◽

Cited By ~ 6

Author(s):

D. Wunderlich ◽

A. Lee ◽

R.P. Fracasso ◽

D.V. Mierz ◽

R.M. Bayney ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Fusion Proteins ◽

Recombinant Fusion Proteins ◽

Rapid Characterization

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Localization of Epitopes for Monoclonal Antibodies Directed against the Adult Rat Skeletal Muscle Sodium Channel (rSkM1) Using Polymerase Chain Reaction, Fusion Proteins, and Western Blotting

Analytical Biochemistry ◽

10.1006/abio.1995.1210 ◽

1995 ◽

Vol 226 (1) ◽

pp. 188-191 ◽

Cited By ~ 2

Author(s):

W.J. Sun ◽

S.A. Cohen ◽

R.L. Barchi

Keyword(s):

Skeletal Muscle ◽

Polymerase Chain Reaction ◽

Monoclonal Antibodies ◽

Sodium Channel ◽

Western Blotting ◽

Fusion Proteins ◽

Rat Skeletal Muscle ◽

Chain Reaction ◽

Adult Rat ◽

Polymerase Chain

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The Instability of Dimeric Fc-Fusions Expressed in Plants Can Be Solved by Monomeric Fc Technology

Frontiers in Plant Science ◽

10.3389/fpls.2021.671728 ◽

2021 ◽

Vol 12 ◽

Author(s):

Pia Gattinger ◽

Shiva Izadi ◽

Clemens Grünwald-Gruber ◽

Somanath Kallolimath ◽

Alexandra Castilho

Keyword(s):

Monoclonal Antibodies ◽

Fusion Proteins ◽

Degradation Products ◽

Therapeutic Proteins ◽

Cost Effective ◽

Full Length ◽

Peptide Sequence ◽

Reporter Protein ◽

The Stability

The potential therapeutic value of many proteins is ultimately limited by their rapid in vivo clearance. One strategy to limit clearance by metabolism and excretion, and improving the stability of therapeutic proteins, is their fusion to the immunoglobulin fragment crystallizable region (Fc). The Fc region plays multiple roles in (i) dimerization for the formation of “Y”-shaped structure of Ig, (ii) Fc-mediated effector functions, (iii) extension of serum half-life, and (iv) a cost-effective purification tag. Plants and in particular Nicotiana benthamiana have proven to be suitable expression platforms for several recombinant therapeutic proteins. Despite the enormous success of their use for the production of full-length monoclonal antibodies, the expression of Fc-fused therapeutic proteins in plants has shown limitations. Many Fc-fusion proteins expressed in plants show different degrees of instability resulting in high amounts of Fc-derived degradation products. To address this issue, we used erythropoietin (EPO) as a reporter protein and evaluated the efforts to enhance the expression of full-length EPO-Fc targeted to the apoplast of N. benthamiana. Our results show that the instability of the fusion protein is independent from the Fc origin or IgG subclass and from the peptide sequence used to link the two domains. We also show that a similar instability occurs upon the expression of individual heavy chains of monoclonal antibodies and ScFv-Fc that mimic the “Y”-shape of antibodies but lack the light chain. We propose that in this configuration, steric hindrance between the protein domains leads to physical instability. Indeed, mutations of critical residues located on the Fc dimerization interface allowed the expression of fully stable EPO monomeric Fc-fusion proteins. We discuss the limitations of Fc-fusion technology in N. benthamiana transient expression systems and suggest strategies to optimize the Fc-based scaffolds on their folding and aggregation resistance in order to improve the stability.

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