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Dario Neri - One of the best experts on this subject based on the ideXlab platform.
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Abstract 5553: A novel immunocytokine for the treatment of cancer
Cancer Research, 2018Co-Authors: Mattia Matasci, Sarah Wulhfard, Emanuele Puca, Tiziano Ongaro, Alessandra Villa, Dario NeriAbstract:Interleukin-12 (IL12) is an immunomodulatory cytokine, which offers unique opportunities for cancer therapy due to its stimulatory function on cell-mediated immunity and its anti-angiogenic activity. IL12 was shown to polarize CD4+ T cells into a TH1 type and to be a key activator of NK cells and CD8+ T cells. It also induces the production of interferon-gamma by T cells and NK cells and subsequently of the anti-angiogenic chemokines CXCL10/IP-10, and CXCL9/Mig. However the potent anti-tumor IL12 activity, which has been reported in mice, has not yet been successfully translated into clinical development, mainly because of early reports of severe toxicity and low response rates in human. Following our pioneering work which started in 2002 with the first description of an IL12 based antibody-cytokine fusion protein (i.e. Immunocytokine), we have extensively explored and perfected alternative molecular formats, with the aim to further improve biodistribution properties and therapeutic activity of IL12-based immunocytokines. Here we describe the development and evaluation of new targeted variants of both murine and human IL-12 with enhanced therapeutic efficacy and improved safety profile. To this end we combined the immunomodulatory properties of the IL12 payload with the tumor-homing activity of the L19 antibody. L19 is a clinical grade fully human antibody, which recognizes with identical affinity in both mouse and human, the alternatively spliced EDB domain of fibronectin. EDB represent an optimal target for anti-cancer pharmacodelivery, due to its pan-tumoral over-expression nature combined with very low expression levels in normal tissues. This has also been confirmed by extensive Nuclear Medicine work in which radiolabeled L19 has been administered to more than 150 patients, making L19 one of the best validated tumor-targeting agent. Our novel immunocytokine, termed IL12-L19-L19, relies on the L19 antibody in tandem diabody format, with a monomeric IL12 moiety expressed as single-chain polypeptide at the N-terminal extremity. Recombinant IL12-L19-L19 proteins based either on human or murine IL12, were efficiently expressed in CHO cells and purified to high quality. The tumor-targeting properties of both variants were validated in tumor-bearing mice, using radioiodinated protein preparations. In preclinical therapy studies IL12-L19-L19 showed potent anti-cancer activity when used either as single agent or in combination with other anticancer agents. PK studies in Cynomolgus Monkey using the fully human IL12-L19-IL19 product, revealed a favorable profile, which is compatible with other clinical-stage immunocytokines based on antibody-fragments. These results strongly support the further development of the fully human IL12-L19-L19 product for future clinical investigations. Citation Format: Mattia Matasci, Emanuele Puca, Tiziano Ongaro, Sarah Wulhfard, Alessandra Villa, Dario Neri. A novel immunocytokine for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5553.
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The antibody-based targeted delivery of interleukin-4 and 12 to the tumor neovasculature eradicates tumors in three mouse models of cancer
International Journal of Cancer, 2014Co-Authors: Teresa Hemmerle, Dario NeriAbstract:Preclinical studies with recombinant murine interleukin 4 (IL4) in models of cancer have shown potent tumor growth inhibition. However, systemic administration of human IL4 to cancer patients exhibited modest antitumor activity and considerable toxicities. To improve the therapeutic index and reduce side effects of this cytokine, we developed of a novel "immunocytokine" based on sequential fusion of murine IL4 with the antibody fragment F8 (specific to the alternatively spliced extra-domain A of fibronectin, a marker for tumor-angiogenesis) in diabody format. The resulting fusion protein, termed F8-IL4, retained full antigen-binding activity and cytokine bioactivity and was able to selectively localize on solid tumors in vivo. When used as single agent, F8-IL4 inhibited tumor growth in three different immunocompetent murine cancer models (F9 teratocarcinoma, CT26 colon carcinoma and A20 lymphoma). Furthermore, F8-IL4 showed synergistic effects when coadministered with immunocytokines based on IL2 and IL12. Indeed, combination therapy with an IL12-based immunocytokine yielded complete tumor eradication, in spite of the fact that IL4 and IL12 display opposite immunological mechanisms of action in terms of their polarization of T-cell based responses. No weight loss or any signs of toxicity were observed in treated mice, both in monotherapy and in combination, indicating a good tolerability of the immunocytokine treatment. Interestingly, mice cured from CT26 tumors acquired a durable protective antitumor immunity. Depletion experiments indicated that the antitumor activity was mediated by CD8+ T cells and by NK cells.
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The antibody-based delivery of interleukin-12 to the tumor neovasculature eradicates murine models of cancer in combination with paclitaxel
Clinical Cancer Research, 2012Co-Authors: Nadine Pasche, Elisa Carugati, Sarah Wulhfard, Francesca Pretto, Dario NeriAbstract:PURPOSE: Interleukin-12 (IL12) is a potent proinflammatory cytokine with antitumor activity. Its heterodimeric nature makes it compatible with a large variety of different immunocytokine formats. Here we report the design, production, and characterization of a novel immunocytokine, based on the fusion of the F8 antibody (specific to the alternatively spliced EDA domain of fibronectin, a marker of tumor neovasculature) with IL12 (termed IL12-F8-F8).\n\nEXPERIMENTAL DESIGN: We developed a novel immunocytokine based on the sequential fusion of interleukin-12 as a single polypeptide with two F8 antibodies in single-chain Fv (scFv) format. The fusion protein was characterized in vitro, and its targeting performance was assessed in vivo. The immunocytokine antitumor activity was studied as monotherapy as well as in combination therapies in three different murine tumor models. Moreover, depletion experiments and tumor analysis revealed a dominant role of natural killer cells for the mechanism of action.\n\nRESULTS: IL12-F8-F8 can be produced in mammalian cells, yielding a product of good pharmaceutical quality, capable of selective localization on the tumor neovasculature in vivo, as judged by quantitative biodistribution analysis with radioiodinated protein preparations. The protein potently inhibited tumor growth in three different immunocompetent syngeneic models of cancer. The treatment was generally well tolerated. Moreover, the IL12-F8-F8 fusion protein could be produced both with murine IL12 (mIL12) and with human IL12 (hIL12).\n\nCONCLUSIONS: The potent antitumor activity of mIL12-F8-F8, studied alone or in combination with paclitaxel in different tumor models, paves the way to the clinical development of the fully human immunocytokine.
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An engineered antibody-interleukin-12 fusion protein with enhanced tumor vascular targeting properties
International Journal of Cancer, 2006Co-Authors: Verena Gafner, Eveline Trachsel, Dario NeriAbstract:The antibody-mediated targeted delivery of interleukin-12 (IL12) to the EDB domain of fibronectin, a marker of angiogenesis, is a promising avenue for enhancing the therapeutic index of this anti-cancer cytokine. Previous experiments, based on sequential fusion of a single-chain IL12 derivative to the anti-EDB antibody fragment scFv(L19) had yielded a therapeutic fusion protein [IL12-scFv(L19)-FLAG], which displayed an impressive therapeutic activity in murine models of cancer, in spite of a tumor uptake, which was less efficient compared to the parental unmodified scFv(L19). In this article, we describe the comparative analysis of 3 recombinant fusion proteins comprising the scFv(L19) and IL12 moieties. One of them, in which the p40 and p35 form a covalent heterodimer and in which each subunit is fused to a molecule of scFv(L19), displays an excellent tumor targeting performance in vivo, as assessed by quantitative biodistribution analysis, and a potent anti-tumor effect, superior to the one of IL12-scFv(L19)-FLAG. These results may have a clinical impact, considering the fact that the tumor targeting ability of scFv(L19) in patients with cancer has been demonstrated using scintigraphic methods, and that 2 scFv(L19)-based antibody-cytokine fusion are currently entering clinical trials.
Sofia A Oliveira - One of the best experts on this subject based on the ideXlab platform.
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brief report association of ccr1 klrc4 IL12A as1 stat4 and erap1 with behcet s disease in iranians
Arthritis & Rheumatism, 2015Co-Authors: Ines Sousa, Farhad Shahram, David Francisco, Fereydoun Davatchi, Bahar Sadeghi Abdollahi, Fahmida Ghaderibarmi, Abdolhadi Nadji, Niloofar Mojarad Shafiee, Joana M Xavier, Sofia A OliveiraAbstract:Objective To independently replicate the top findings from 4 published genome-wide association studies (GWAS) of susceptibility genes in Behcet's disease (BD). Methods We tested 14 single-nucleotide polymorphisms (SNPs) in 13 genomic loci (excluding the major histocompatibility complex [MHC], IL10, and IL23R–IL12RB2, which have already been associated with BD in Iranians) for allelic and genotypic associations with BD in 973 patients and 828 controls from Iran and performed meta-analyses of the significantly associated markers. Results Six SNPs (in decreasing order of significance, rs7616215 located 38 kb downstream of CCR1, rs2617170 [p.Asn104Ser] in KLRC4, rs17810546 in IL12A–AS1, rs7574070 in STAT4, and rs10050860 [p.Asp575Asn] and rs13154629 in ERAP1) were nominally associated with BD in both allelic association tests (5.05 × 10−9 ≤ Pallele ≤ 7.55 × 10−3) and sex-adjusted genotypic association tests (6.01 × 10−9 ≤ adjusted P value ≤ 1.30 × 10−2). For all 6 SNPs tested by meta-analysis (Pmeta), the association with BD was strengthened, because the direction and magnitude of association were similar across populations (e.g., for rs7574070, odds ratio [OR] for A allele 1.29 [95% confidence interval (95% CI) 1.21–1.37], Pmeta = 2.34 × 10−16; for rs7616215, OR for C allele 0.70 [95% CI 0.65–0.76], Pmeta = 1.54 × 10−19; for rs17810546, OR for A allele 0.60 [95% CI 0.52–0.70], Pmeta = 6.34 × 10−11; for rs2617170, OR for T allele 0.76 [95% CI 0.70–0.81], Pmeta = 2.75 × 10−14; for rs13154629, OR for TT genotype 2.76 [95% CI 2.01–3.80], Pmeta = 3.57 × 10−10). Conclusion This study reinforces the notion that CCR1, KLRC4, IL12A–AS1, STAT4, and ERAP1 are bona fide susceptibility genes for BD, in addition to the MHC, IL10, and IL23R–IL12RB2 loci. Future genetic and functional studies are now warranted to uncover the roles of these genes in the pathogenesis of BD.
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Brief Report: Association of CCR1, KLRC4, IL12A–AS1, STAT4, and ERAP1 With Behçet's Disease in Iranians
Arthritis & Rheumatism, 2015Co-Authors: Ines Sousa, Farhad Shahram, David Francisco, Fereydoun Davatchi, Bahar Sadeghi Abdollahi, Fahmida Ghaderibarmi, Abdolhadi Nadji, Niloofar Mojarad Shafiee, Joana M Xavier, Sofia A OliveiraAbstract:Objective To independently replicate the top findings from 4 published genome-wide association studies (GWAS) of susceptibility genes in Behcet's disease (BD). Methods We tested 14 single-nucleotide polymorphisms (SNPs) in 13 genomic loci (excluding the major histocompatibility complex [MHC], IL10, and IL23R–IL12RB2, which have already been associated with BD in Iranians) for allelic and genotypic associations with BD in 973 patients and 828 controls from Iran and performed meta-analyses of the significantly associated markers. Results Six SNPs (in decreasing order of significance, rs7616215 located 38 kb downstream of CCR1, rs2617170 [p.Asn104Ser] in KLRC4, rs17810546 in IL12A–AS1, rs7574070 in STAT4, and rs10050860 [p.Asp575Asn] and rs13154629 in ERAP1) were nominally associated with BD in both allelic association tests (5.05 × 10−9 ≤ Pallele ≤ 7.55 × 10−3) and sex-adjusted genotypic association tests (6.01 × 10−9 ≤ adjusted P value ≤ 1.30 × 10−2). For all 6 SNPs tested by meta-analysis (Pmeta), the association with BD was strengthened, because the direction and magnitude of association were similar across populations (e.g., for rs7574070, odds ratio [OR] for A allele 1.29 [95% confidence interval (95% CI) 1.21–1.37], Pmeta = 2.34 × 10−16; for rs7616215, OR for C allele 0.70 [95% CI 0.65–0.76], Pmeta = 1.54 × 10−19; for rs17810546, OR for A allele 0.60 [95% CI 0.52–0.70], Pmeta = 6.34 × 10−11; for rs2617170, OR for T allele 0.76 [95% CI 0.70–0.81], Pmeta = 2.75 × 10−14; for rs13154629, OR for TT genotype 2.76 [95% CI 2.01–3.80], Pmeta = 3.57 × 10−10). Conclusion This study reinforces the notion that CCR1, KLRC4, IL12A–AS1, STAT4, and ERAP1 are bona fide susceptibility genes for BD, in addition to the MHC, IL10, and IL23R–IL12RB2 loci. Future genetic and functional studies are now warranted to uncover the roles of these genes in the pathogenesis of BD.
Rodney J Scott - One of the best experts on this subject based on the ideXlab platform.
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IL12A mphosph9 cdk2ap1 and rgs1 are novel multiple sclerosis susceptibility loci
Genes and Immunity, 2010Co-Authors: Federica Esposito, Nikolaos A Patsopoulos, Sabine Cepok, Ingrid Kockum, Virpi Leppa, David R Booth, Robert Heard, Graeme Stewart, Rodney J ScottAbstract:A recent meta-analysis identified seven single-nucleotide polymorphisms (SNPs) with suggestive evidence of association with multiple sclerosis (MS). We report an analysis of these polymorphisms in a replication study that includes 8,085 cases and 7,777 controls. A meta-analysis across the replication collections and a joint analysis with the discovery data set were performed. The possible functional consequences of the validated susceptibility loci were explored using RNA expression data. For all of the tested SNPs, the effect observed in the replication phase involved the same allele and the same direction of effect observed in the discovery phase. Three loci exceeded genome-wide significance in the joint analysis: RGS1 (P value=3.55 × 10−9), IL12A (P=3.08 × 10−8) and MPHOSPH9/CDK2AP1 (P=3.96 × 10−8). The RGS1 risk allele is shared with celiac disease (CD), and the IL12A risk allele seems to be protective for celiac disease. Within the MPHOSPH9/CDK2AP1 locus, the risk allele correlates with diminished RNA expression of the cell cycle regulator CDK2AP1; this effect is seen in both lymphoblastic cell lines (P=1.18 × 10−5) and in peripheral blood mononuclear cells from subjects with MS (P=0.01). Thus, we report three new MS susceptibility loci, including a novel inflammatory disease locus that could affect autoreactive cell proliferation.
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IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci
Genes and Immunity, 2010Co-Authors: Federica Esposito, Nikolaos A Patsopoulos, Sabine Cepok, Ingrid Kockum, Virpi Leppa, David R Booth, Robert Heard, Graeme Stewart, Rodney J ScottAbstract:A recent meta-analysis identified seven single-nucleotide polymorphisms (SNPs) with suggestive evidence of association with multiple sclerosis (MS). We report an analysis of these polymorphisms in a replication study that includes 8,085 cases and 7,777 controls. A meta-analysis across the replication collections and a joint analysis with the discovery data set were performed. The possible functional consequences of the validated susceptibility loci were explored using RNA expression data. For all of the tested SNPs, the effect observed in the replication phase involved the same allele and the same direction of effect observed in the discovery phase. Three loci exceeded genome-wide significance in the joint analysis: RGS1 (P value=3.55 × 10−9), IL12A (P=3.08 × 10−8) and MPHOSPH9/CDK2AP1 (P=3.96 × 10−8). The RGS1 risk allele is shared with celiac disease (CD), and the IL12A risk allele seems to be protective for celiac disease. Within the MPHOSPH9/CDK2AP1 locus, the risk allele correlates with diminished RNA expression of the cell cycle regulator CDK2AP1; this effect is seen in both lymphoblastic cell lines (P=1.18 × 10−5) and in peripheral blood mononuclear cells from subjects with MS (P=0.01). Thus, we report three new MS susceptibility loci, including a novel inflammatory disease locus that could affect autoreactive cell proliferation.
Robert P Myers - One of the best experts on this subject based on the ideXlab platform.
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primary biliary cirrhosis associated with hla IL12A and il12rb2 variants
The New England Journal of Medicine, 2009Co-Authors: Gideon M. Hirschfield, Chun Xu, Xiangjun Gu, Kaiyan Jing, Brian D Juran, Andrew L Mason, Erin Walker, Yan Lu, Yue Lu, Robert P MyersAbstract:Background Primary biliary cirrhosis is a chronic granulomatous cholangitis, characteristically associated with antimitochondrial antibodies. Twin and family aggregation data suggest that there is a significant genetic predisposition to primary biliary cirrhosis, but the susceptibility loci are unknown. Methods To identify genetic loci conferring a risk for primary biliary cirrhosis, we carried out a genomewide association analysis in which DNA samples from 2072 Canadian and U.S. subjects (536 patients with primary biliary cirrhosis and 1536 controls) were genotyped for more than 300,000 single-nucleotide polymorphisms (SNPs). Sixteen of the SNPs most strongly associated with primary biliary cirrhosis were genotyped in two independent replication sets. We carried out fine-mapping studies across three loci associated with primary biliary cirrhosis. Results We found significant associations between primary biliary cirrhosis and 13 loci across the HLA class II region; the HLA-DQB1 locus (encoding the major h...
Ines Sousa - One of the best experts on this subject based on the ideXlab platform.
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brief report association of ccr1 klrc4 IL12A as1 stat4 and erap1 with behcet s disease in iranians
Arthritis & Rheumatism, 2015Co-Authors: Ines Sousa, Farhad Shahram, David Francisco, Fereydoun Davatchi, Bahar Sadeghi Abdollahi, Fahmida Ghaderibarmi, Abdolhadi Nadji, Niloofar Mojarad Shafiee, Joana M Xavier, Sofia A OliveiraAbstract:Objective To independently replicate the top findings from 4 published genome-wide association studies (GWAS) of susceptibility genes in Behcet's disease (BD). Methods We tested 14 single-nucleotide polymorphisms (SNPs) in 13 genomic loci (excluding the major histocompatibility complex [MHC], IL10, and IL23R–IL12RB2, which have already been associated with BD in Iranians) for allelic and genotypic associations with BD in 973 patients and 828 controls from Iran and performed meta-analyses of the significantly associated markers. Results Six SNPs (in decreasing order of significance, rs7616215 located 38 kb downstream of CCR1, rs2617170 [p.Asn104Ser] in KLRC4, rs17810546 in IL12A–AS1, rs7574070 in STAT4, and rs10050860 [p.Asp575Asn] and rs13154629 in ERAP1) were nominally associated with BD in both allelic association tests (5.05 × 10−9 ≤ Pallele ≤ 7.55 × 10−3) and sex-adjusted genotypic association tests (6.01 × 10−9 ≤ adjusted P value ≤ 1.30 × 10−2). For all 6 SNPs tested by meta-analysis (Pmeta), the association with BD was strengthened, because the direction and magnitude of association were similar across populations (e.g., for rs7574070, odds ratio [OR] for A allele 1.29 [95% confidence interval (95% CI) 1.21–1.37], Pmeta = 2.34 × 10−16; for rs7616215, OR for C allele 0.70 [95% CI 0.65–0.76], Pmeta = 1.54 × 10−19; for rs17810546, OR for A allele 0.60 [95% CI 0.52–0.70], Pmeta = 6.34 × 10−11; for rs2617170, OR for T allele 0.76 [95% CI 0.70–0.81], Pmeta = 2.75 × 10−14; for rs13154629, OR for TT genotype 2.76 [95% CI 2.01–3.80], Pmeta = 3.57 × 10−10). Conclusion This study reinforces the notion that CCR1, KLRC4, IL12A–AS1, STAT4, and ERAP1 are bona fide susceptibility genes for BD, in addition to the MHC, IL10, and IL23R–IL12RB2 loci. Future genetic and functional studies are now warranted to uncover the roles of these genes in the pathogenesis of BD.
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Brief Report: Association of CCR1, KLRC4, IL12A–AS1, STAT4, and ERAP1 With Behçet's Disease in Iranians
Arthritis & Rheumatism, 2015Co-Authors: Ines Sousa, Farhad Shahram, David Francisco, Fereydoun Davatchi, Bahar Sadeghi Abdollahi, Fahmida Ghaderibarmi, Abdolhadi Nadji, Niloofar Mojarad Shafiee, Joana M Xavier, Sofia A OliveiraAbstract:Objective To independently replicate the top findings from 4 published genome-wide association studies (GWAS) of susceptibility genes in Behcet's disease (BD). Methods We tested 14 single-nucleotide polymorphisms (SNPs) in 13 genomic loci (excluding the major histocompatibility complex [MHC], IL10, and IL23R–IL12RB2, which have already been associated with BD in Iranians) for allelic and genotypic associations with BD in 973 patients and 828 controls from Iran and performed meta-analyses of the significantly associated markers. Results Six SNPs (in decreasing order of significance, rs7616215 located 38 kb downstream of CCR1, rs2617170 [p.Asn104Ser] in KLRC4, rs17810546 in IL12A–AS1, rs7574070 in STAT4, and rs10050860 [p.Asp575Asn] and rs13154629 in ERAP1) were nominally associated with BD in both allelic association tests (5.05 × 10−9 ≤ Pallele ≤ 7.55 × 10−3) and sex-adjusted genotypic association tests (6.01 × 10−9 ≤ adjusted P value ≤ 1.30 × 10−2). For all 6 SNPs tested by meta-analysis (Pmeta), the association with BD was strengthened, because the direction and magnitude of association were similar across populations (e.g., for rs7574070, odds ratio [OR] for A allele 1.29 [95% confidence interval (95% CI) 1.21–1.37], Pmeta = 2.34 × 10−16; for rs7616215, OR for C allele 0.70 [95% CI 0.65–0.76], Pmeta = 1.54 × 10−19; for rs17810546, OR for A allele 0.60 [95% CI 0.52–0.70], Pmeta = 6.34 × 10−11; for rs2617170, OR for T allele 0.76 [95% CI 0.70–0.81], Pmeta = 2.75 × 10−14; for rs13154629, OR for TT genotype 2.76 [95% CI 2.01–3.80], Pmeta = 3.57 × 10−10). Conclusion This study reinforces the notion that CCR1, KLRC4, IL12A–AS1, STAT4, and ERAP1 are bona fide susceptibility genes for BD, in addition to the MHC, IL10, and IL23R–IL12RB2 loci. Future genetic and functional studies are now warranted to uncover the roles of these genes in the pathogenesis of BD.
