targeted-toxins

Bryder D, Konturk-Ciesla A, Zhang Q, Kharazi S (2024) A non-invasive stem cell therapy boosts lymphopoiesis and averts age-related blood diseases in mice. Research Square doi: 10.21203/rs.3.rs-4528815/v1

Objective: To develop a murine transplantation model based on low-intensity conditioning protocols using antibody-mediated Hematopoietic stem cell.

Summary: Authors demonstrate that young HSCs, once transplanted, survive and thrive in aged hosts, dramatically improving hematopoietic output and ameliorating age-compromised lymphopoiesis.

Usage: Intravenous injection of CD45-SAP (3 mg/kg, IT-91). Biotinylated anti-CD45.2 antibodies were mixed with streptavidin-saporin conjugate at a 1:1 molar ratio (IT-27).

Related Products: Anti-CD45.2-SAP (Cat. #IT-91), Streptavidin-ZAP (Cat. #IT-27)

Ciuro M, Sangiorgio M, Cacciato V, Cantone G, Fichera C, Salvatorelli L, Magro G, Leanza G, Vecchio M, Valle MS, Gulino R (2024) Mitigating the functional deficit after neurotoxic motoneuronal loss by an inhibitor of mitochondrial fission. Int J Mol Sci 25(13):7059. doi: 10.3390/ijms25137059 PMID: 39000168

Objective: To use the Cholera Toxin B-Saporin (CTB-SAP) mouse animal model of Amyotrophic lateral sclerosis (ALS) to determine the efficacy of mitochondrial division inhibitor 1 (Mdivi-1) for its potential neuroprotective effect.

Summary: Mdivi-1 reduced motor deficits in the ALS model. It also showed neuroprotective effects on motoneurons and promoted plasticity. This could represent a translational approach for motoneuron disorders.

Usage: To establish the model, mice received two injections of the retrogradely transported, ribosome-inactivating toxin, CTB-SAP (Cat. #IT-14) into the medial and lateral right gastrocnemius muscles, respectively, with a toxin dose of 6 μg/2 μL in PBS per injection.

Related Products: CTB-SAP (Cat. #IT-14)

Kang Y, Toyoda H, Saito M (2024) Search for unknown neural link between the masticatory and cognitive brain systems to clarify the involvement of its impairment in the pathogenesis of Alzheimer’s disease. Front Cell Neurosci 18:1425645. doi: 10.3389/fncel.2024.1425645 PMID: 38994328

Summary: It remains unclear how masticatory dysfunction can induce brain degeneration similar to Alzheimer’s Disease (AD), and the neural mechanism linking the trigeminal nervous system responsible for mastication and the cognitive and memory brain system remains unknown. In this review paper, authors provide clues to the search for such “missing link” by discussing the embryological, anatomical, and physiological relationship between locus coeruleus (LC) and its laterally adjoining mesencephalic trigeminal nucleus which plays a central role in the masticatory functions.

Usage: To clarify the role of BFC neurons such as in nucleus basalis of Meyner (NBM) in AD pathogenesis, selective lesioning of basal forebrain cholinergic (BFC) neurons was made using the immunotoxin mu p75-SAP (IT-16) in such transgenic mice. The lesioning of BFC neurons resulted in an earlier appearance of Aβ accumulation and memory impairment in the cortex and hippocampus.

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

See Also:

• Laursen B et al. Cholinergic degeneration is associated with increased plaque deposition and cognitive impairment in APPswe/PS1dE9 mice. Behav Brain Res 240:146-152, 2013.
• Ramos-Rodriguez JJ et al. Rapid beta-amyloid deposition and cognitive impairment after cholinergic denervation in app/ps1 mice. J Neuropathol Exp Neurol 72(4):272-285, 2013.

Garaudé S (2024) Engineering an antibody-discernible and functional CD45 variant on hematopoietic stem and progenitor cells via base editing. Univ Basel Thesis.

Objective: To develop a system for a cell surface marker present on all hematopoietic cell to deplete malignant cells. Authors screened CD45’s extracellular domain regions with base editors and generated multiple CD45 protein variants altering the binding of antibodies.

Summary: Authors selected the CD45 K352E/G variant profile and improved its base editing rate as it showcased loss of binding of a unique anti-CD45 antibody while still maintaining the surface marker’s expression, stability, and function in human hematopoietic stem and progenitor cells (HSPCs). The resulting loss of antibody binding prompted the modification and humanization of the anti-CD45 antibody, culminating in the development of an anti-CD45 antibody-drug conjugate (CD45-ADC; CIM053-SG3376). In an AML mouse models xenografted with HSPCs, administration of the CD45-ADC selectively depleted human leukemia and HSPCs wt cells while preserving the healthy hematopoietic system derived from the transplanted base edited HSPCs.

Usage: In vitro antibody-drug-conjugate (ADC) mediated killing assays. For ADC killing assays involving saporin, a 100 nM stock was prepared by incubating the biotinylated antibody and Streptavidin-ZAP at a 1:1 molar ratio for 30 min at room temperature

Related Products: Streptavidin-ZAP (Cat. #IT-27), Anti-CD45.2-SAP (Cat. #IT-91)

Garaudé S, Marone R, Lepore R, Devaux A, Beerlage A, Seyres D, Dell’ Aglio A, Juskevicius D, Zuin J, Burgold T, Wang S, Katta V, Manquen G, Li Y, Larrue C, Camus A, Durzynska I, Wellinger LC, Kirby I, Van Berkel PH, Kunz C, Tamburini J, Bertoni F, Widmer CC, Tsai SQ, Simonetta F, Urlinger S, Jeker LT (2024) Selective haematological cancer eradication with preserved haematopoiesis. Nature 630(8017):728-735. doi: 10.1038/s41586-024-07456-3 PMID: 38778101

Objective: To demonstrate that an antibody–drug conjugate (ADC) targeting the pan-haematopoietic marker CD45 enables the antigen-specifc depletion of the entire haematopoietic system, including Haematopoietic stem cells ( HSC).

Summary: Pairing this ADC with the transplantation of human HSCs engineered to be shielded from the CD45-targeting ADC enables the selective eradication of leukaemic cells with preserved haematopoiesis. The combination of CD45-targeting ADCs and engineered HSCs creates an almost universal strategy to replace a diseased haematopoietic system, irrespective of disease aetiology or originating cell type.

Usage: For ADC killing assays involving saporin, a 100 nM stock was prepared by incubating the biotinylated antibody (BC8 or MIRG451 mAbs) and saporin–streptavidin (IT-27) at a 1:1 molar ratio for 30 min at room temperature

Related Products: Anti-CD45.2-SAP (Cat. #IT-91), Streptavidin-ZAP (Cat. #IT-27)

Jin H, Li M, Jeong E, Castro-Martinez F, Zuker CS (2024) A body–brain circuit that regulates body inflammatory responses. Nature 630(8017):695-703. doi: 10.1038/s41586-024-07469-y PMID: 38692285

Objective: To show that a peripheral immune insult strongly activates the body–brain axis to regulate immune responses.

Summary: Using Anti-DBH-SAP, the authors demonstrate that pro-inflammatory and anti-inflammatory cytokines communicate with distinct populations of vagal neurons to inform the brain of an emerging inflammatory response. In turn, the brain tightly modulates the course of the peripheral immune response. Genetic silencing of this body–brain circuit produced unregulated and out-of-control inflammatory responses. By contrast activating this circuit affords neural control of immune responses.

Usage: Bilateral injection into the caudal nucleus of the solitary tract of mice with Anti-DBH–SAP (IT-03, 20 ng per side).

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

Barioni NO, Beduschi RS, da Silva AV, Martins MG, Almeida-Francia CCD, Rodrigues SA, López DE, Gómez-Nieto R, Horta-Júnior JAC (2024) The role of the ventral nucleus of the trapezoid body in the auditory prepulse inhibition of the acoustic startle reflex. Hearing Research doi: 10.1016/j.heares.2024.109070 PMID: 38972084

Objective: To study the acoustic startle response through elimination of the ventral nucleus of the trapezoid body neurons via Anti-ChAT-SAP injection.

Summary: The elimination of ventral nucleus of the trapezoid body (VNTB) is used while measuring the auditory prepulse inhibition and acoustic startle response with and without this group of neurons to study their role in rats. It was found The VNTB stands as the sole identified source of cholinergic inputs to Cochlear root neurons.

Usage: Lesions in the VNTB were performed via a bilateral microinjection of a neurotoxin selective for cholinergic neurons, the anti-ChAT-saporin (IT-42, 0.25 ug/μl, 400 nL)

Related Products: Anti-ChAT-SAP (Cat. #IT-42)

Collins HM, Greenfield S (2024) Rodent models of alzheimer’s disease: Past misconceptions and future prospects. Int J Mol Sci 25(11):6222. doi: 10.3390/ijms25116222 PMID: 38892408

Objective: To outline the various apparent causes of Alzheimer’s Disease (AD) and evaluate the success or otherwise of their reproduction in rodents.

Summary: To understand the pathogenesis of AD and how it progresses through the brain, the authors describe the need of an animal model that reproduces the causal mechanism driving the disease. For decades, researchers have attempted to model AD by recapitulating downstream markers of its pathology, including cholinergic neuron loss, Aβ and tau aggregation, and neuroinflammation. Insights gained from the study of Parkinson’s Disease (PD) show that we must model the actual neurodegenerative mechanisms of AD in adult, wildtype animals by specifically targeting the neural populations first affected by a disease. The authors propose an alternative model, based on the aberrant accumulation of the novel peptide T14. In the review, specific cholinergic neuron degeneration was produced by 192 IgG-saporin, which resulted in degeneration of cholinergic cell bodies and terminals via apoptotic cell death.

See Also:

• Book AA et al. 192 IgG-saporin: I. Specific lethality for cholinergic neurons in the basal forebrain of the rat. J Neuropathol Exp Neurol 53:95-102, 1994.
• McGaughy J et al. The role of cortical cholinergic afferent projections in cognition: impact of new selective immunotoxins. Behav Brain Res 115:251-263, 2000.
• Holley LA et al. Cortical cholinergic deafferentation following the intracortical infusion of 192-IgG-saporin: a quantitative histochemical study. Brain Res 663:277-286, 1994.

Nishioka M, Hata T (2024) Cholinergic interneurons in the dorsal striatum play an important role in the acquisition of duration memory. Eur J Neurosci 59(11):3061-3073. doi: 10.1111/ejn.16337 PMID: 38576223

Objective: To investigate duration-memory formation in the dorsal striatum.

Summary: Rats were sufficiently trained using a peak-interval 20s procedure and then infused with anti-choline acetyltransferase–saporin into the dorsal striatum to cause selective ablation of cholinergic interneurons. Lesions of the cholinergic cells show delayed memory acquisition and suggest dorsal striatum neurons play a role in new duration memory.

Usage: Each group of rats received aCSF or anti-choline acetyltransferase (ChAT)–saporin (Anti-ChAT-SAP, IT-42) at 0.5 μg/μL at 0.5 μl/min for 2 mins.

Related Products: Anti-ChAT-SAP (Cat. #IT-42)

Nirogi R, Jayarajan P, Benade V, Abraham R, Goyal VK (2024) Hits and misses with animal models of narcolepsy and the implications for drug discovery. Expert Opin Drug Discov 19(6):755-768. doi: 10.1080/17460441.2024.2354293 PMID: 38747534

Objective: To review the usage of Orexin-B-SAP treated rats in the development of drug candidates for the treatment of narcolepsy.

Summary: Examines pharmacological agents used for the modeling of narcolepsy in animals and contrasts it with narcolepsy expression in real patients. Additionally summarizes the discovery of the orexin system in narcolepsy and how animal models aided in that discovery.

Usage: Orexin- B-saporin (IT-20) was injected into the lateral hypothalamus of rats.

Related Products: Orexin-B-SAP (Cat. #IT-20)