targeted-toxins

Dedoni S, Olianas A, Manconi B, Collu M, Tuveri B, Vincis ME, Olianas MC, Onali P (2022) Upregulation of p75NTR by histone deacetylase inhibitors sensitizes human neuroblastoma cells to targeted immunotoxin-induced apoptosis. Int J Mol Sci 23(7):3849. doi: 10.3390/ijms23073849 PMID: 35409209

Summary: Histone deacetylase (HDAC) inhibitors have been useful chemotherapy agents in the treatment of neuroblastomas, the most frequent solid tumor of childhood. Studies have shown that the expression of the neurotrophin receptor, p75NTR, on human neuroblastoma cells are enhanced after exposure to some HDAC inhibitors. The authors used mu p75-SAP along with two HDAC inhibitors, valproic acid and entinostat, to investigate if they could exploit the upregulation of p75NTR and see if these cells were more susceptible as a target for elimination. The administration of mu p75-SAP only induced cell death in tumors of mice that were pretreated with entinostat

Usage: Cells were treated for 24 hr with entinostat and then exposed to 30 nM of mu p75-SAP for 24 hr.

Related Products: mu p75-SAP (Cat. #IT-16)

Charlesworth CT, Hsu I, Wilkinson AC, Nakauchi H (2022) Immunological barriers to haematopoietic stem cell gene therapy. Nat Rev Immunol 1-15. doi: 10.1038/s41577-022-00698-0

Objective: This review article attempts to encourage more research to address the immunological barriers to haematopoietic stem cell based gene therapies.

Summary: The authors lay out the history and clinical trials of hematopoietic stem cell gene therapy and then discuss the challenges of both innate immunity and adaptive immunity.

Usage: This review mentions a publication that used Anti-CD117-SAP to ablate hematopoietic stem cells.

Related Products: Anti-CD117-SAP (Cat. #IT-83)

See Also:

• Czechowicz A et al. Selective hematopoietic stem cell ablation using CD117-antibody-drug-conjugates enables safe and effective transplantation with immunity preservation. Nat Commun 10:617, 2019.

Saha A, Hyzy S, Lamothe T, Hammond K, Clark N, Lanieri L, Bhattarai P, Palchaudhuri R, Gillard GO, Proctor J, Riddle MJ, Panoskaltsis-Mortari A, MacMillan ML, Wagner JE, Kiem HP, Olson LM, Blazar BR (2022) A CD45-targeted antibody-drug conjugate successfully conditions for allogeneic hematopoietic stem cell transplantation in mice. Blood 139(11):1743-1759. doi: 10.1182/blood.2021012366 PMID: 34986233

Objective: To investigate the effectiveness of a CD45-targeted antibody-drug conjugate (ADC) in conditioning for allogeneic hematopoietic stem cell transplantation (HSCT) in mice.

Summary: In this study, researchers evaluated a novel CD45-targeted antibody-drug conjugate as a conditioning regimen for allogeneic hematopoietic stem cell transplantation in mice. The results demonstrated successful conditioning, highlighting the potential of this approach for improving the outcomes of allogeneic HSCT in the future.

Related Products: Anti-CD117-SAP (Cat. #IT-83)

See Also:

• Palchaudhuri R et al. Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin. Nat Biotechnol 34:738-745, 2016.
• Czechowicz A et al. Selective hematopoietic stem cell ablation using CD117-antibody-drug-conjugates enables safe and effective transplantation with immunity preservation. Nat Commun 10:617, 2019.
• Li Z et al. Hematopoietic chimerism and donor-specific skin allograft tolerance after non-genotoxic CD117 antibody-drug-conjugate conditioning in MHC-mismatched allotransplantation. Nat Commun 10:616, 2019.
• Gao C et al. Nongenotoxic antibody-drug conjugate conditioning enables safe and effective platelet gene therapy of hemophilia A mice. Blood Adv 3(18):2700-2711, 2019.
• Castiello MC et al. Efficacy and safety of anti-CD45-saporin as conditioning agent for RAG deficiency. J Allergy Clin Immunol 147(1):309-320.e6, 2021.

Yun-Fei L, Zhang J, Wang XQ, Peng JJ, Ling BF, Liu FT, Yang F, Dong G, Yu YQ (2022) Noradrenergic innervations of the medial prefrontal cortex mediate empathy for pain in rats via the α1 and β receptors. Behav Brain Res 10:113828. doi: 10.1016/j.bbr.2022.113828

Objective: To study the roles of the locus coeruleus (LC) to medial prefrontal cortex (mPFC) pathway in pain empathy in rats.

Summary: Results indicate that noradrenergic innervations in the mPFC mediate empathy for pain in rats via the α1 and β receptors.

Usage: Noradrenergic innervations of the mPFC were selectively eliminated through intra-mPFC injections of Anti-DBH-SAP.

Related Products: Anti-DBH-SAP (Cat. #IT-03)

Pereira PM, Papy-Garcia D, Barritault D, Chiappini F, Jackisch R, Schimchowitsch S, Cassel JC (2022) Protective Effects of a synthetic glycosaminoglycan mimetic (OTR4132) in a rat immunotoxic lesion model of septohippocampal cholinergic degeneration. Glycoconj J 39(1):107-130. doi: 10.1007/s10719-022-10047-x PMID: 35254602

Objective: Assess the effects of OTR4132, a synthetic heparan-mimetic biopolymer that is designed to have neuroprotective/neurotrophic properties.

Summary: 192-IgG-SAP was used to create a partial hippocampal cholinergic denervation model. Rats were also injected with OTR4132, either intramuscularly (1.5 mg/kg) or into the lateral ventricle (0.25ug/5 ul/rat). Rats injected with 192-IgG-SAP showed decreases in (1) hippocampal acetylcholinesterase reaction products and in (2) choline acetyltransferase-positive neurons in the medial septum. Both these attributes were significantly lessened in rats treated with OTR4132.

Usage: 192-IgG-SAP was injected into the medial septum/diagonal band of broca (0.37 ug) of Long-Evans male rats.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Ramezani F, Salehian S, Hosseinzadeh S, Mahjour Z, Babajani T, Ghorbanian D, Feizi F, Pourbagher R (2022) Serotonin-1A receptor activation in the median raphe nucleus improves response learning-based strategy in 192IgG saporin-induced cognitive impairments. Eur J Pharmacol 918:174774. doi: 10.1016/j.ejphar.2022.174774 PMID: 35077674

Objective: Investigating the role of Serotonin-1A receptors in spatial navigation.

Summary: 192-IgG-SAP was used to selectively eliminate cholinergic neurons in the brain as a model for deficits found in Alzheimer’s Disease. The spatial navigation skills of the rats treated with 192-IgG-SAP were compared against those that were treated with Saporin in conjunction with another serotonin-1A antagonist or auto receptor stimulant to find the role of serotonin in the median raphe nucleus in movement.

Usage: Selective cholinergic denervation was achieved by intracerebroventricular administration of 192-IgG-SAP (IT-01, 1.0 μl/each ventricle at the rate of 0.2 μl/min ) on male Wistar rats.

Related Products: 192-IgG-SAP (Cat. #IT-01)

McDonough KE (2022) Maintenance mechanism of nociplastic pain in males. University of Texas Medical Branch Thesis.

Objective: The objective of this dissertation is to elucidate the sex-specific mechanisms underlying the transition to and maintenance of a nociplastic pain state using animal models.

Summary: This PhD dissertation investigates the mechanisms underlying the transition from acute to chronic nociplastic pain using murine models. The study finds that in males, spinal microglial activation driven by GABAergic disinhibition allows normally innocuous stimulation to induce a transition to nociplastic pain maintained by spinal microglia and proinflammatory cytokines.

Usage: Intrathecal injection of Saporin or Mac-1-SAP at 8.85 μM.

Related Products: Mac-1-SAP mouse/human (Cat. #IT-06), Saporin (Cat. #PR-01)

Ancheta LR, Shramm PA, Bouajram R, Higgins D, Lappi DA (2022) Saporin as a commercial reagent: its uses and unexpected impacts in the biological sciences-tools from the plant kingdom. Toxins (Basel) 14(3):184. doi: 10.3390/toxins14030184 PMID: 35324681

Summary: Saporin is a ribosome-inactivating protein that can cause inhibition of protein synthesis and causes cell death when delivered inside a cell. Development of commercial Saporin results in a technology termed ‘molecular surgery’, with Saporin as the scalpel. Its low toxicity (it has no efficient method of cell entry) and sturdy structure make Saporin a safe and simple molecule for many purposes. The most popular applications use experimental molecules that deliver Saporin via an add-on targeting molecule. These add-ons come in several forms: peptides, protein ligands, antibodies, even DNA fragments that mimic cell-binding ligands. Cells that do not express the targeted cell surface marker will not be affected. This review will highlight some newer efforts and discuss significant and unexpected impacts on science that molecular surgery has yielded over the last almost four decades. There are remarkable changes in fields such as the Neurosciences with models for Alzheimer’s Disease and epilepsy, and game-changing effects in the study of pain and itch. Many other uses are also discussed to record the wide-reaching impact of Saporin in research and drug development.

Read complete article.

Xu L, Füredi N, Lutter C, Geenen B, Pétervári E, Balaskó M, Dénes Á, Kovács KJ, Gaszner B, Kozicz T (2022) Leptin coordinates efferent sympathetic outflow to the white adipose tissue through the midbrain centrally-projecting Edinger-Westphal nucleus in male rats. Neuropharmacology 205:108898. doi: 10.1016/j.neuropharm.2021.108898

Objective: To show that leptin bound to neurons of the Edinger-Westphal nucleus (EWcp) stimulated STAT3 phosphorylation and increases urocortin 1 (Ucn1)-production in a time-dependent manner.

Summary: EWcp/LepRb/Ucn1 neurons respond to leptin signaling as well as control white adipose tissue size and fat metabolism without altering food intake.

Usage: Ablation of EWcp leptin receptor (LepRb) positive neurons with leptin-saporin. Either unconjugated saporin (53 ng in 80 nl MQ, or Leptin-SAP (90 ng in 80 nl MQ, was injected into the rat midbrain.

Related Products: Leptin-SAP (Cat. #IT-47), Saporin (Cat. #PR-01)

Hankerd K, McDonough KE, Wang J, Tang SJ, Chung JM, La JH (2022) Postinjury stimulation triggers a transition to nociplastic pain in mice. Pain 163(3):461-473. doi: 10.1097/j.pain.0000000000002366 PMID: 34285154

Objective: To facilitate studies on the underlying mechanisms of nociplastic pain, authors developed a mouse model in which postinjury thermal stimulation prolongs capsaicin (ie, experimental injury)-induced transient mechanical hypersensitivity outside of the injury area.

Summary: Results demonstrate that postinjury stimulation of the injured area can trigger the transition from transient pain to nociplastic pain more readily in females, and sex-dependent mechanisms maintain the nociplastic pain state.

Usage: A single intrathecal injection of unconjugated saporin (PR-01) or Mac-1-saporin (IT-06, 8.85 μM, 5 μL).

Related Products: Mac-1-SAP mouse/human (Cat. #IT-06), Saporin (Cat. #PR-01)