Biotherapeutics: Challenges and Opportunities for Predictive Toxicology of Monoclonal Antibodies

Abstract

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.

Extended half-life target module for sustainable UniCAR T-cell treatment of STn-expressing cancers

“…For that, the scFv derived from the mAb L2A5 and the E5B9 epitope were fused to the human IgG4 hinge and Fc region. The backbone of the IgG4 molecule was chosen due to the limited binding to Fc receptors as well as the weak or absent activation of both complement and antibodydependent cellular cytotoxicity [29]. As a result, IgG4 antibodies have been widely used to design therapeutic antibodies when a weak or absent immune cell activation is desired, yet maintaining an increased plasmatic half-life comparable to the other IgG subclasses [30].…”

ProtDCal‐Suite: A web server for the numerical codification and functional analysis of proteins

“…The capability of ProtDCal to generate useful features was assessed in several studies developing novel machine learning-based tools. [9][10][11][12][13][14][15][16][17][18][19] Here, we present web interfaces for predicting the interaction likelihood of protein-protein and protein-peptide pairs (PPI-Detect), for identifying enzymes from amino acid sequences or 3D structures (Enzyme Identifier), and for predicting N-glycosylation sites in peptides and proteins (Pred-NGlyco).…”

“…In this context, ProtDCal is a software package that transforms protein sequences or 3D‐structures into general‐purpose numerical descriptors, accounting for both global and local information . Due to its complementary performance with respect to other well‐established tools in the field like PROFEAT and PseAcc (later extended to Pse‐in‐one), ProtDCal has been used in a number of studies . Notable among them are the modeling of posttranslational modifications, the prediction of protein enzymatic function, the prediction of antimicrobial activity in peptides, the determination of residues critical for protein function, and the prediction of stability changes upon mutations .…”

“…5 Due to its complementary performance with respect to other well-established tools in the field like PROF-EAT 6 and PseAcc 7 (later extended to Pse-in-one 8 ), ProtDCal has been used in a number of studies. [9][10][11][12][13][14][15][16][17][18][19] Notable among them are the modeling of posttranslational modifications, 14 the prediction of protein enzymatic function, 15 the prediction of antimicrobial activity in peptides, 16 the determination of residues critical for protein function, 17 and the prediction of stability changes upon mutations. 18 Very recently, ProtDCal was enhanced with a procedure for encoding protein pairs, which allows targeting the protein-protein interaction identification problem.…”

An Immunological Outlook on SARS Coronavirus (SARS-CoV-2) and Its Current Clinical Status

“…Description Mode of action of the drug Remdesivir [41] Antiviral Inhibiting RNA synthesis by adenosine nucleotide analogue in coronaviruses Chloroquine [42] Antiparasitic and antirheumatic Interferes with glycosylation of SARS-CoV cellular receptors Favipiravir [43] Antiviral used against influenza Inhibits the RNA-dependent RNA polymerase of RNA viruses Lopinavir [44] Antiviral, immune suppression A protease inhibitor; inhibits RNA replication and release of virus from host cell. Also inhibits the action of 3CL-protease Sarilumab [45] Human monoclonal antibody against interleukin-6 receptor Slows down the process of cytokine release, thus preventing organ damage ASC-09 + ritonavir [46] Antiviral A protease inhibitor, inhibits RNA replication Tocilizumab [42] Human monoclonal antibody against interleukin-6 receptor Slows down the process of cytokine release, thus preventing organ damage Lenzilumab [47] Humanized monoclonal antibody for relieving pneumonia Acts against cytokine release syndrome Dapagliflozin [48,49] Sodium-glucose cotransporter 2 inhibitor…”