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Transforming Growth Factor-α and Epidermal Growth Factor
Published in Jason Kelley, Cytokines of the Lung, 2022
In a number of situations, TGF-α appears to be a superagonist, compared with EGF. TGF-α is 10–100 times more potent than EGF in stimulating prostacyclin (PGI2) secretion by cultured human umbilical vein endothelial cells, despite that TGF-α and EGF are equipotent mitogens for these cells (Ristimaki, 1989). Although both TGF-α and EGF are equipotent in their capacity to induce anchorage-independent growth of NRK fibroblasts (Anzano et al., 1983), TGF-α is more potent than EGF in stimulating human pancreatic cancer cells in the same assay (Smith et al., 1987). In vivo, TGF-α is a superagonist, compared with EGF, in stimulating angiogenesis (Schreiber et al., 1986), in accelerating wound healing (Schultz et al., 1987), and in promoting mouse mammary gland development (Vonderhaar, 1987).
Secretion of Epidermal Growth Factor and Transforming Growth Factor α by Normal and Malignant Cells
Published in Velibor Krsmanović, James F. Whitfield, Malignant Cell Secretion, 2019
As already mentioned, TGF-α and EGF exhibit a remarkably similar mode of interaction with the EGF receptor, although, on a molar basis, purified TGF-α has only about half the receptor-binding affinity of EGF.30 TGF-α and EGF are equally potent stimulators of the protein tyrosine kinase activity of the A431 cell EGF receptor,31 and upon prolonged exposure, they induce down-regulation of the receptor.31 Both factors are equally active in inducing eyelid opening in newborn mice.33 TGF-α is also more potent than EGF in inducing monolayer colony formation of epidermal cells, a process which is dependent on cell migration.34In vivo, TGF-α is more potent than EGF in promoting angiogenesis35 and stimulating hair follicle development.36 TGF-α is also more active than EGF in the induction of Ca2+ release from bone in culture.37 Thus, TGF-α and EGF behave differently in several biological systems, and in many cases TGF-α is much more potent than EGF and acts as a superagonist. However, it is not yet understood why these two factors, which bind to the same receptor, can trigger differential responses. Further studies on receptor-ligand interaction and the subsequent physiological intracellular events are obviously required to understand the differential activities of TGF-α and EGF.
Melanotropin Receptors: Studies with Labeled Melanotropins
Published in Mac E. Hadley, The Melanotropic Peptides, 2018
Alex N. Eberle, Pierre N. E. de Graan, Walter Siegrist, Jürg Girard
[Nle4,D-Phe7]α-MSH, a superagonist of α-MSH inducing long-lasting pigment dispersion similar to photoaffinity labeling,51 has been shown to bind to the receptor also in the absence of calcium.52 This means that calcium is not a necessary prerequisite for MSH-receptor binding. A comparison of the long-lasting response of Anolis melanophores induced by photoreactive [Pap13]α-MSH with that elicited by [Nle4,D-Phe7]α-MSH demonstrated that repetitive exposure of the skins to calcium-free buffer removed the latter, but not the former (Figure 6).53 It appears, therefore, that the superagonist did indeed bind to the receptor in calcium-free medium when the proportion of free hormone was in a large excess relative to the receptors. When, however, the ratio approached unity, the superagonist was less tightly bound in calcium-free buffer than the covalently bound photoreactive peptide. Nevertheless, it is interesting to note that the change in configuration at position 7 reduces the calcium dependence of MSH-receptor binding, but not of receptor-adenylate cyclase coupling.
The triple function of the capsaicin-sensitive sensory neurons: In memoriam János Szolcsányi
Published in Temperature, 2023
Erika Pintér, Zsuzsanna Helyes, Éva Szőke, Kata Bölcskei, Angéla Kecskés, Gábor Pethő
The selective, high affinity SST4 receptor agonist J-2156 is a non-peptide sulfonamidopeptidomimetic (1ʹS,2S)-4-amino-N-(1’-carbamoyl-2’-phenylethyl)-2-(4”-methyl-1”naphthalenesulfonamino)-butanamide. This compound was synthesized by Juvantia Pharma (Turku, Finland). J-2156 binds to the human SST4 receptor with nanomolar affinity, which exceeds the binding affinity of native SOM, and shows nearly 400-fold selectivity for SST4 compared to the other SST receptors [29]. In a cAMP assay indicating receptor activation, it behaved as a full agonist similar to native SOM-14 or SOM-28. In another G-protein activation functional assay, it produced 2.5-fold stronger responses than native SOM. Based on these properties, this molecule was considered as a “superagonist” [29]. Further in vitro studies showed that J-2156 does not cause desensitization after repeated administration, an important consideration for the potential therapeutic use of this compound [30].
Non-human primates in the PKPD evaluation of biologics: Needs and options to reduce, refine, and replace. A BioSafe White Paper
Published in mAbs, 2022
Karelle Ménochet, Hongbin Yu, Bonnie Wang, Jay Tibbitts, Cheng-Pang Hsu, Amrita V. Kamath, Wolfgang F. Richter, Andreas Baumann
Targeting the CD28 pathway has been considered high risk since 2006, when TeGenero’s CD28 superagonist mAb (TGN1412) caused severe cytokine release syndrome resulting in long-term damage in 6 healthy volunteers during a Phase 1 clinical trial.40, 41 Using a pharmacologically based method to establish the FIH starting dose, such as the MABEL approach, is recommended for targets that likely lead to a biological cascade or cytokine release with an amplification.7 As an antagonist, lack of agonism or costimulatory activity and inhibiting CD28-mediated T-cell proliferation and cytokine production, lulizumab pegol was not anticipated to cause any amplified cytokine release.42 However, given the inherent risk of targeting CD28, a MABEL approach was conservatively adopted to select the FIH starting dose.43 The challenges associated with the MABEL approach included: 1) assessing potential differences of sensitivity for the mode of action (preferably under physiological relevant conditions) between human and animals; 2) identifying a relevant animal model to establish in vitro to in vivo correlation in target engagement (e.g., dissociation constant (Kd), receptor occupancy (RO), and concentration leading to 50% of maximum effect (EC50)); and 3) identifying a translational PD marker for functional activities. This example illustrates how the NHP PKPD data, including systemic exposure, extent of RO, PD activities, and duration of effect, played a critical role in the FIH dose selection.
Immunotherapy and non-muscle-invasive bladder cancer: an idea from the 19th century
Published in Expert Review of Anticancer Therapy, 2021
VB4-845 (Vicinium TM), a recombinant fusion protein, permits cell death, displaying immunogenicity in tumor cells, and favors clearance by the immune system [29]. Studies have investigated this agent through intravesical administration in BCG-unresponsive NMIBC, proving a complete response at 3 months of 40%; response being maintained thereafter, sparing patients from cystectomy [30]. N-803, an Il-15 superagonist, has been studied in the phase 2/3 QUILT 3.032 trial (NCT03022825) [31]. Seventy-two percent of recruited patients with BCG-unresponsive NMIBC proved complete response, the latter has scored to date a median of 19.2 months [32]. Nadofaragene firadenovec (Adstiladrin TM) is an adenovirus vector harboring recombinant IFN alpha 2 with antitumor activity [33]. It has proven to be tolerated with few side effects, and demonstrated a complete response in 53% of patients with BCG-unresponsive NMIBC, response was maintained at 12 months in a relatively significant subset of these patients [34].