Author: Schewe, Denis M. ; Winterberg, Dorothee ; Poirier, Nicolas ; Alten, Julia ; Neyton, Stéphanie ; Pengam, Sabrina ; Narbeburu, Emma ; Mary, Caroline ; Schüler, Thomas ; Peipp, Matthias ; Lenk, Lennart ; Dietterle, Anna ; Schrappe, Martin ; den Boer, Monique L. ; Boer, Judith M. ; Baccelli, Irène ; Wessels, Wiebke ; Déramé, Mylène ; Taurelle, Julien ; Bourquin, Jean-Pierre ; Bornhauser, Beat ; Cario, Gunnar ; Reimer, Claas ; Escherich, Gabriele ; Raffel, Simon ; Heymann, Julia ; Antić, Željko ; Brüggemann, Monika ; Laqua, Anna ; Dovhan, Vladyslava ; Corallo, Frédérique ; Vogiatzi, Fotini ; Bergmann, Anke K.

AbstractAcute lymphoblastic leukemia (ALL) arises from the uncontrolled proliferation of B-cell precursors (BCP-ALL) or T cells (T-ALL). Current treatment protocols obtain high cure rates in children but are based on toxic polychemotherapy. Novel therapies are urgently needed, especially in relapsed/refractory (R/R) disease, high-risk (HR) leukemias and T-ALL, in which immunotherapy approaches remain scarce. Although the interleukin-7 receptor (IL-7R) plays a pivotal role in ALL development, no IL-7R–targeting immunotherapy has yet reached clinical application in ALL. The IL-7Rα chain (CD127)–targeting IgG4 antibody lusvertikimab (LUSV; formerly OSE-127) is a full antagonist of the IL-7R pathway, showing a good safety profile in healthy volunteers. Here, we show that ∼85% of ALL cases express surface CD127. We demonstrate significant in vivo efficacy of LUSV immunotherapy in a heterogeneous cohort of BCP- and T-ALL patient-derived xenografts (PDX) in minimal residual disease (MRD) and overt leukemia models, including R/R and HR leukemias. Importantly, LUSV was particularly effective when combined with polychemotherapy in a phase 2-like PDX study with CD127high samples leading to MRD-negativity in >50% of mice treated with combination therapy. Mechanistically, LUSV targeted ALL cells via a dual mode of action comprising direct IL-7R antagonistic activity and induction of macrophage-mediated antibody-dependent cellular phagocytosis (ADCP). LUSV–mediated in vitro ADCP levels significantly correlated with CD127 expression levels and the reduction of leukemia burden upon treatment of PDX animals in vivo. Altogether, through its dual mode of action and good safety profile, LUSV may represent a novel immunotherapy option for any CD127+ ALL, particularly in combination with standard-of-care polychemotherapy.

15 Aug 1992·Journal of immunology (Baltimore, Md. : 1950)

Retinoic acid and phorbol ester synergistically up-regulate IL-8 expression and specifically modulate protein kinase C-epsilon in human skin fibroblasts.

Article

Author: Burns, D ; Ceska, M ; Voorhees, J J ; Fisher, G J ; Baldassare, J J ; Zhang, Q Y ; Hammerberg, C ; Henderson, P A

Phorbol ester (TPA) and retinoic acid (RA) are two potent immunomodulatory agents whose actions are mediated through distinct signal transduction pathways involving protein kinase C (PKC) and nuclear RA receptors, respectively. We have investigated the interactions between these two pathways in the regulation of expression of the inflammatory cytokine IL-8 in human skin fibroblasts. TPA (as previously reported) and RA both induced IL-8 mRNA and protein in a time- and dose-dependent manner. IL-8 mRNA induction by TPA (10 nM) was maximal (15-fold) within 6 h, and returned to baseline within 24 h of treatment, although maximal induction (10-fold) by RA (1 microM) did not occur until 24 h posttreatment. Induction of IL-8 by TPA was blocked by 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine, which inhibits PKC and cAMP-dependent protein kinases (PKA), but not by N-(2-ganidinoethyl)-5-isoquinoline sulfonamide, which preferentially inhibits PKA, consistent with the participation of PKC in the induction of IL-8 by TPA. In contrast, induction of IL-8 by RA was inhibited by both 1-(5-isoquinoline sulfonamide and N-(2-gamidinoethyl)-5-isoquinoline sulfonamide, suggesting the participation of PKA in the induction of IL-8 by RA. However, activation of PKA by addition of cAMP analogues was not sufficient to induce IL-8 expression. Induction of IL-8 by RA also did not appear to be mediated indirectly through induction of IL-1, because addition of IL-1R antagonist did not block IL-8 induction by RA. RA and TPA added in combination synergistically enhanced expression of IL-8 mRNA, measured at 6 (2-fold) and 24 h (10-fold) posttreatment. To investigate the mechanism of this synergy, the effect of TPA and RA on fibroblast PKC activation and PKC isozyme levels were determined. TPA, either alone or together with RA, but not RA alone, stimulated phosphorylation of an endogenous 80-kDa PKC substrate. Dermal fibroblasts expressed three PKC isozymes (alpha, (delta, and (epsilon). TPA, but not RA, down-regulated PKC-alpha, neither TPA or RA affected the level of PKC-delta, and both TPA and RA down-regulated PKC-epsilon. This latter effect was enhanced 2-fold by addition of RA and TPA together. These data suggest that modulation of PKC-epsilon may be a common participant in the regulation of IL-8 expression by TPA and RA.

01 Jul 1986·Immunology

Characterization by a monoclonal antibody and functional analysis of a subset of bovine T lymphocytes that express BoT8, a molecule analogous to human CD8.

Article

Author: Ellis, J A ; Baldwin, C L ; Goddeeris, B M ; MacHugh, N D ; Morrison, W I ; Bensaid, A ; Teale, A J

Monoclonal antibody (mAb) IL-A17 characterizes a subset of bovine T lymphocytes. IL-A17 recognizes a 34,000-35,000 MW doublet, designated BoT8, which is expressed on the surface of approximately 20% of peripheral blood mononuclear leucocytes (PBM), a subpopulation of lymphocytes in T-dependent areas of lymph nodes and spleen, and about 70% of thymocytes. This molecule is not expressed on B lymphocytes, monocytes/macrophages or granulocytes. Double labelling of PBM showed that the BoT8+ population is distinct from the T lymphocyte subset expressing BoT4. BoT8+ lymphocytes purified with a fluorescence-activated cell sorter (FACS) proliferated poorly in response to mitogenic and alloantigenic stimulation in the absence of exogenous growth factors. IL-A17 had no inhibitory effect on proliferation of PBM to mitogens (Con A and PHA) or alloantigens and no measurable effect on the in vitro generation of cytolytic effector cells. However, in some experiments IL-A17 was found to block partially allospecific cytolytic function mediated by bulk effector cell populations when included in 51Cr-release assays. Fractionation of effector cells generated in an allogeneic mixed leucocyte culture (MLC) demonstrated that cytotoxic cells specific for class I major histocompatibility complex (MHC) antigens reside within the BoT8+ population. Based on these data, and information reported elsewhere on alloreactive bovine T-cell clones, BoT8 is considered to be analogous to CD8 in humans and equivalent molecules in other species.

100 Deals associated with IL-1R7 antagonist (Icanomab)

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammation	Preclinical	AT	Icanomab Gmbh	11 Mar 2024
Asthma	Preclinical	DE	Icanomab Gmbh	14 May 2021
COVID-19	Preclinical	DE	Icanomab Gmbh	14 May 2021
Gout	Preclinical	DE	Icanomab Gmbh	14 May 2021
Inflammatory Bowel Diseases	Preclinical	DE	Icanomab Gmbh	14 May 2021
Macrophage Activation Syndrome	Preclinical	DE	Icanomab Gmbh	14 May 2021
Respiratory Distress Syndrome, Acute	Preclinical	DE	Icanomab Gmbh	14 May 2021

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