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Valutazione dell’immunotossicità per il nuovo inibitore della tirosin-chinasi della milza R406

Posted on Giugno 15, 2022Giugno 22, 2022 by Andrea
  1. Spleen tyrosine kinase (Syk) is a novel pharmaceutical target in the treatment of allergic, autoimmune and neoplastic diseases. Previous studies have shown that Syk signaling plays a key role in regulating the lymphohematopoietic system. These observations prompted us to investigate whether Syk’s inhibition promoted immunotoxicity.
  2. In a series of studies,  rats  were given orally R406 at doses up to and including 100 mg / kg / day (or its prodrug R788 at doses up to and including 100 mg / kg / day, reduced to 50 mg / day). ). kg / day for women after passing MTD), a strong Syk inhibitor, twice daily for 28 days.
  3. Oltre alle valutazioni tossicologiche standard, sono stati eseguiti test di immunofenotipizzazione citometrica a flusso e di risposta immunitaria umorale misurando i livelli di  anticorpi IgM   e IgG  anti  –  KLH  .  Altri studi di immunotossicità includevano tre modelli di resistenza dell’ospite in topi Balb/c femmine per determinare ulteriormente gli effetti di R406 sull’immunità innata e acquisita.
  4. Dopo il trattamento con R406,  negli studi sui ratti sono stati osservati gli effetti immunomodulatori attesi (ad es. diminuzione del peso del timo e della milza, perdita di cellule del midollo osseo e diminuzione della conta dei linfociti, inclusi i linfociti T e B). Questi cambiamenti si sono generalmente risolti dopo un periodo di recupero di 14 giorni senza trattamento  . KLH   challenge   nei   ratti non   ha mostrato  effetti  avversi sulla risposta IgG o   IgM   . R788/406, somministrato per via orale a dosi fino a 80 mg/kg/die inclusi per 28 giorni, non ha influenzato la clearance batterica o virale nei modelli di resistenza murina rispettivamente di Listeria, streptococco o ospiti dell’influenza.
  5. Ciò era correlato a precedenti test di funzionalità dei macrofagi e dei neutrofili in vitro (valutazione di ioni migratori, fagocitosi, scoppio ossidativo e attività battericida) che hanno mostrato che  l’ R406  non ha influenzato negativamente la funzione dei macrofagi o dei neutrofili nelle risposte immunitarie innate. Presi insieme, questi risultati mostrano che l’  R406  ha un’immunotossicità funzionale minima nonostante i suoi effetti linfocitopenici, suggerendo che l’inibizione di Syk potrebbe non portare a effetti avversi inaccettabili basati sui meccanismi.

Valutazione dell’immunotossicità per il nuovo inibitore della tirosin-chinasi della milza R406.

    • Cdna 8Spleen tirosin chinasi (Syk) è un nuovo target farmaceutico nel  trattamento delle malattie allergiche, autoimmuni e cancerose. Precedenti studi hanno dimostrato che la segnalazione Syk svolge un ruolo chiave nella regolazione del sistema linfoematopoietico.
    • Queste osservazioni ci hanno spinto a indagare se l’inibizione di Syk promuovesse l’immunotossicità. In una serie di studi   , ai ratti è   stato somministrato per via orale R406 a dosi fino a 100 mg/kg/die inclusi (o il suo profarmaco R788 a dosi fino a 100 mg/kg/die inclusi, ridotti a 50 mg/die). kg/die per le donne dopo aver superato la MTD), un forte inibitore Syk, due volte al giorno per 28 giorni.
    • In addition to standard toxicological assessments     , flow cytometric immunophenotyping and humoral immune response tests were performed by measuring levels of  anti   –   KLH  IgM    and IgG antibodies   .  Other immunotoxicity studies included three host resistance models in female Balb / c mice to further determine the effects of R406 on innate and acquired immunity.
    • After treatment with R406,   the expected immunomodulatory effects (e.g. decreased thymus and spleen weight, loss of bone marrow cells and decreased lymphocyte counts, including T and B lymphocytes) were observed in rat studies. .
    • These changes generally resolved during the 14-day treatment-free recovery period. KLH    challenge    in    rats  showed   no adverse effects on IgG or IgM   response       . R788 / 406, administered orally at doses up to and including 80 mg / kg / day for 28 days, did not affect bacterial or viral clearance in mouse resistance models of Listeria, streptococcus or influenza hosts, respectively.
    • This was related to previous in vitro macrophage and neutrophil function tests (evaluation of migratory ions, phagocytosis, oxidative burst and bactericidal activity) which showed that  R406   did not adversely affect macrophage or neutrophil function in immune responses. innate.
    • Taken together, these results show that   R406   has minimal functional immunotoxicity despite its lymphocytopenic effects, suggesting that Syk inhibition may not lead to unacceptable mechanism-based adverse effects.

 

To test whether IL-10 acts as an autocrine or paracrine growth factor for Ly-1 B cells, we treated mice continuously from birth to 8 weeks of age with a rat   monoclonal IgM antibody    that  specifically neutralizes      IL-10. murine. Mice treated in this manner were deprived of   peritoneal Ly-1 B cells, contained significantly reduced serum levels of immunoglobulin M, and were unable to generate  significant in vivo antibody responses   to intraperitoneal injection of alpha 1,3-dextran or phosphorylcholine,  antigens   , for which specific B cells are found in the subset of Ly-1 B cells.

In contrast, spleen B cells from  conventional anti   -IL-10-treated mice were normal with respect to total number, phenotype, and in vitro response to B cell mitogens and     trinitrophenyl hemocyanin antigen (TNP-   KLH )   from thymus-dependent keyhole patella. ).

The mechanism of Ly-1 B cell depletion appears to be related to increased levels of endogenous interferon gamma (IFN-gamma) in mice treated with anti-IL-10 because they   co-administered   anti-IFN-gamma sub anti   –   IL. – 10 neutralizing  antibodies    .  alli restored the number of Ly-1 B cells residing in the peritoneum of these mice.

In contrast, spleen B cells from  conventional anti   -IL-10-treated mice were normal with respect to total number, phenotype, and in vitro response to B cell mitogens and     trinitrophenyl hemocyanin antigen (TNP-   KLH )   from thymus-dependent keyhole patella. ).

The mechanism of Ly-1 B cell depletion appears to be related to increased levels of endogenous interferon gamma (IFN-gamma) in mice treated with anti-IL-10 because they   co-administered   anti-IFN-gamma sub anti   –   IL. – 10 neutralizing  antibodies    .  alli restored the number of Ly-1 B cells residing in the peritoneum of these mice. These results suggest that IL-10 is a growth regulator of Ly-1 B cells and identify a procedure for specific depletion of Ly-1 B cells, thus allowing further evaluation of the role of these cells in the immune system.

Anti-Calnexin antibody (KLH)

STJ97891 100 µl 234 EUR

Anti-Calregulin antibody (KLH)

STJ97892 100 µl 234 EUR

Anti-cAMP antibody (KLH)

STJ97893 100 µl 234 EUR

Anti-CD20 antibody (KLH)

STJ97914 100 µl 234 EUR

Anti-Clenbuterol antibody (KLH)

STJ97960 100 µl 234 EUR

Anti-Flag antibody (KLH)

STJ98077 100 µl 234 EUR

Anti-MTAP Antibody (KLH)

STJ503536 100 µg 586 EUR

Mouse Keyhole Limpet Hemocyanin (KLH IgM) ELISA Kit

abx053480-96tests 96 tests 668 EUR

Human Anti-Meningococcal Group A/C/W/Y Oligosaccharides IgM (Combo) ELISA Kit, 96 tests, Quantitative

600-884-IGM 1 Kit 1017 EUR

Human Anti-Keyhole limpet hemocyanin (KLH) IgM ELISA Kit, 96 tests, Quantitative

700-145-KLM 1 Kit 773 EUR

Mouse Anti-Keyhole limpet hemocyanin (KLH) IgM ELISA Kit, 96 tests, Quantitative

700-155-VAM 1 Kit 712 EUR

Monkey Anti-Keyhole limpet hemocyanin (KLH) IgM ELISA Kit, 96 tests, Quantitative

700-180-KLM 1 Kit 773 EUR

Canine Anti-Keyhole limpet hemocyanin (KLH) IgM ELISA Kit, 96 tests, Quantitative

700-190-KLM 1 Kit 773 EUR

Rat(anti-CMV IgM)

QY-E11747 96T 374 EUR

Rabbit anti Rat IgM

40C-CB1264 2 mg 285 EUR

Goat anti Rat IgM

40C-CB1271 1 mg 363 EUR

Rat anti Mouse IgM

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Mouse anti Rat IgM

41R-1122 100 ug 265 EUR

Mouse anti Rat IgM

41R-1123 100 ug 265 EUR

Bovine Immunoglobulin M (IgM) ELISA Kit

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Bovine Immunoglobulin M (IgM) ELISA Kit

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Chicken Immunoglobulin M (IgM) ELISA Kit

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Chicken Immunoglobulin M (IgM) ELISA Kit

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Human Immunoglobulin M (IgM) ELISA Kit

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Human Immunoglobulin M (IgM) ELISA Kit

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Mouse Immunoglobulin M (IgM) ELISA Kit

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Mouse Immunoglobulin M (IgM) ELISA Kit

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Rabbit Immunoglobulin M (IgM) ELISA Kit

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Rabbit Immunoglobulin M (IgM) ELISA Kit

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Bovine Immunoglobulin M (IgM) ELISA Kit

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Bovine Immunoglobulin M (IgM) ELISA Kit

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Chicken Immunoglobulin M (IgM) ELISA Kit

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Chicken Immunoglobulin M (IgM) ELISA Kit

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Human Immunoglobulin M (IgM) ELISA Kit

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Human Immunoglobulin M (IgM) ELISA Kit

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Mouse Immunoglobulin M (IgM) ELISA Kit

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Mouse Immunoglobulin M (IgM) ELISA Kit

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Rabbit Immunoglobulin M (IgM) ELISA Kit

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Rabbit Immunoglobulin M (IgM) ELISA Kit

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Bovine Immunoglobulin M (IgM) ELISA Kit

RD-IgM-b-48Tests 48 Tests 453 EUR

Bovine Immunoglobulin M (IgM) ELISA Kit

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Mouse keyhole limpet hemocyanin (KLH) antibody (IgM) ELISA kit

CSB-E13375m-24T 1 plate of 24 wells 165 EUR

Mouse keyhole limpet hemocyanin (KLH) antibody (IgM) ELISA kit

1-CSB-E13375m
  • 900.00 EUR
  • 5476.00 EUR
  • 2900.00 EUR
  • 1 plate of 96 wells
  • 10 plates of 96 wells each
  • 5 plates of 96 wells each

Human keyhole limpet hemocyanin(KLH) antibody(IgM) ELISA Kit

CSB-E16534h-24T 1 plate of 24 wells 165 EUR

Human keyhole limpet hemocyanin(KLH) antibody(IgM) ELISA Kit

1-CSB-E16534h
  • 900.00 EUR
  • 5476.00 EUR
  • 2900.00 EUR
  • 1 plate of 96 wells
  • 10 plates of 96 wells each
  • 5 plates of 96 wells each

Anti-Ki-67 antibody (KLH)

STJ98194 100 µl 234 EUR

Anti-Ki-67 antibody (KLH)

STJ98195 100 µl 234 EUR

Anti-PARP-1 antibody (KLH)

STJ98308 100 µl 234 EUR

Anti-Actin beta antibody (KLH)

STJ97814 100 µl 234 EUR

Anti-Bcl-2 antibody (KLH)

STJ97860 100 µl 234 EUR

Anti-E alpha antibody (KLH)

STJ98053 100 µl 234 EUR

Anti-Myc-tag antibody (KLH)

STJ90105 200 µl 197 EUR

Anti-His-tag antibody (KLH)

STJ90106 200 µl 197 EUR

Anti-HA-tag antibody (KLH)

STJ90107 200 µl 197 EUR

Anti-FLAG-tag antibody (KLH)

STJ90108 200 µl 197 EUR

Lyophilized Exosome Standards

ExoA375 100 μg 303.5 EUR

Lyophilized Exosome Standards

ExoHT29 100 μg 303.5 EUR

Lyophilized Exosome Standards

ExoMCF7 100 μg 303.5 EUR

Lyophilized Exosome Standards

ExoPC3 100 μg 303.5 EUR

Lyophilized Exosome Standards

ExoPLASMA 100 μg 303.5 EUR

Lyophilized Exosome Standards

ExoUrine 100 μg 303.5 EUR

Human Anti-Keyhole limpet hemocyanin (KLH) IgG+IgM ELISA Kit, 96 tests, Quantitative

700-135-KGM 1 kit 773 EUR

Bovine/Cow Anti-Keyhole limpet hemocyanin (KLH) IgM ELISA Kit, 96 tests, Quantitative

700-205-KLM 1 Kit 712 EUR

Rat KLH ELISA Kit

ERK0075 96Tests 521 EUR

Goat anti-Rat IgM Antibody

abx401442-05mg 0.5 mg 370 EUR

Goat Anti-Rat IgM-AP

LF-SA8011AP 1.0 ml 353 EUR

Goat Anti-Rat IgM-BIOT

LF-SA8011B 1.0 mg 312 EUR

Goat Anti-Rat IgM-FITC

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Goat Anti-Rat IgM-HRP

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Goat Anti-Rat IgM-PE

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Goat Anti-Rat IgM-TXRD

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Goat Anti-Rat IgM-TRITC

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Goat Anti-Rat IgM-UNLB

LF-SA8011U 1.0 mg 261 EUR

Rabbit anti Rat IgM (FITC)

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Rabbit anti Rat IgM (rhodamine)

43C-CB1266 1.5 mg 303 EUR

Rabbit anti Rat IgM (biotin)

43C-CB1268 1.5 mg 368 EUR

Rabbit anti Rat IgM (HRP)

43C-CB1269 1.5 mg 399 EUR

Goat anti Rat IgM (FITC)

43C-CB1272 1 mg 364 EUR

Goat anti Rat IgM (rhodamine)

43C-CB1273 1 mg 402 EUR

Goat anti Rat IgM (biotin)

43C-CB1275 1 mg 389 EUR

Goat anti Rat IgM (HRP)

43C-CB1276 1 mg 445 EUR

Mouse anti Rat IgM (HRP)

43R-1632 100 ug 282 EUR

Mouse anti Rat IgM (HRP)

43R-1633 100 ug 282 EUR

Polyclonal Goat anti-GST α-form

GST-ANTI-1 50 uL 280 EUR
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These results suggest that IL-10 is a growth regulator of Ly-1 B cells and identify a procedure for specific depletion of Ly-1 B cells, thus allowing further evaluation of the role of these cells in the immune system.

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