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Nonclinical safety studies are typically conducted to establish a toxicity profile of a new pharmaceutical in clinical development. Such a profile may encompass multiple differing types of animal studies, or not! Some types of animal studies may not be warranted for a specific program or may only require a limited evaluation if scientifically justified. The goal of this course was to provide a practical perspective on regulatory writing of a dossier(s) using the weight of evidence (WOE) approach for carcinogenicity, drug abuse liability and pediatric safety assessments. These assessments are typically done after some clinical data are available and are highly bespoke to the pharmaceutical being developed. This manuscript will discuss key data elements to consider and strategy options with some case studies and examples. Additionally, US FDA experience with dossier(s) including WOE arguments is discussed. [ABSTRACT FROM AUTHOR]

Small changes in the peptide-major histocompatibility complex (MHC) molecule ligands recognized by antigen-specific T cell receptors (TCRs) can convert fully activating complexes into partially activating or even inhibitory ones. This study examined early TCR-dependent signals induced by such partial agonists or antagonists. In contrast to typical agonist ligands, both an antagonist and several partial agonists stimulated a distinct pattern of λ chain phosphorylation and failed to activate associated ZAP-70 kinase. These results identify a specific step in the early tyrosine phosphorylation cascade that is altered after TCR engagement with modified peptide-MHC molecule complexes. This finding may explain the different biological responses to TCR occupancy by these variant ligands., Both the development of immature thymocytes and the effector activities of mature CD8+ and [CD4.sup.+] T cells are controlled by signals arising from the interaction of clonally distributed receptors (TCRs) [...]

Provides information on T cell receptor (TCR). TCR structure; Phosphorylation of linker proteins; Assembly of signalosome; Activation of transcription factors; Formation of immunological synapse; Cytoskeletal reorganization.

ADAP (adhesion and degranulation-promoting adaptor protein) and SKAP55 (Src kinase-associated phosphoprotein of 55 kDa) are T cell adaptors that mediate inside-out signaling from the T cell antigen receptor to integrins, giving rise to increased integrin affinity/avidity and formation of the immunological synapse between the T cell and the antigen-presenting cell. These two proteins are tightly and constitutively associated with one another, and their ability to interact is required for inside-out signaling. Here we show in an ADAP-deficient Jurkat T cell line that the co-dependence of ADAP and SKAP55 extends beyond their functional and physical interactions and show that SKAP55 protein is unstable in the absence of ADAP. Restoration of ADAP to the ADAP-deficient Jurkat T cell line restores SKAP55 expression by causing a 5-fold decrease in the rate of SKAP55 proteolysis. Inactivation of the Src homology 3 domain of SKAP55, which mediates the association between SKAP55 with ADAP, blocks the protective effect of ADAP. The half-life of SKAP55, in the absence of ADAP, is ∼15-20 min, increasing to 90 min in the presence of ADAP. This is a remarkably rapid rate of turnover for a signaling protein and suggests the possibility that stimuli that signal for the stabilization of SKAP55 may play an important role in T cell adhesion and conjugate formation. [ABSTRACT FROM AUTHOR]

Most oligonucleotide therapeutics use Watson-Crick-Franklin base-pairing hybridization to target RNA and mitigate disease-related protein production. Using targets that were previously inaccessible to small molecules and biologics, synthetic nucleotides have provided treatments for severely debilitating and life-threatening diseases. However, these therapeutics possess unique pharmacologies that require specific considerations for their distribution, clearance, and other clinical pharmacology characteristics. Namely, one hurdle in the drug development of these therapeutics remains the prediction of human dose that results in exposures comparable with or below those seen at no observed adverse effect level in animals. For first-in-human (FIH) clinical trials, this often involves allometric scaling based on body surface area (BSA) or body weight (BW). In this study, we reviewed the current literature and surveyed elements across 16 approved oligonucleotide therapeutic New Drug Applications approved by the U.S. Food and Drug Administration in the period from September 1998 to January 2024, and 89 Investigational New Drug (IND) programs with available FIH clinical trials conducted from January 2015 to January 2024, to understand dose selection in early-stage development of oligonucleotide therapeutics. The surveyed elements across these programs include study design, route of administration, dosing regimen, interspecies scaling approach, and the most sensitive species. Of 89 IND programs and 16 approved therapeutics, intravenous and subcutaneous were the most common route of administration, no observable adverse event levels were frequently derived from nonhuman primates, BSA and BW were adjusted for in similar frequencies, patients were predominantly enrolled in FIH trials, and the most common design was a single or multiple ascending dose trial.

B lymphocytes and T lymphocytes utilize several proteins with common functions to transduce signals from their respective receptors. However, at the hierarchial signalling level of SLP-76 [Src homology 2(SH2) domain-containing leukocyte protein of 76-kDa] and LAT (linker for activation of T cells) in T cells, the only corresponding protein in B cells was known to be BLNK (B cell linker protein). It was thought that perhaps BLNK performed the cognate roles of SLP-76 and LAT in B cells; however, mounting evidence to the contrary revealed that this hypothesis was not robust. Two laboratories have recently described the characterization of a protein expressed in B cells and myeloid cells, alternatively termed NTAL (non-T cell activation linker) or LAB (linker for activation of B cells). NTAL/LAB and LAT may have arisen from a primordial gene-duplicating event, but genes that code for the two proteins do not share a very high degree of sequence identity. Wange discusses the results of the two reports, the evidence for functional homology between LAT and NTAL/LAB, and the possibility that the differences between them might lead to specific clinical therapeutics to manipulate immune cell responses.