Kooperativer Bibliotheksverbund

In: American Journal of Epidemiology, Oxford University Press (OUP), Vol. 93, No. 1 ( 1971-1), p. 55-67

Type of Medium: Online Resource

ISSN: 1476-6256 , 0002-9262

URL: Article

DOI: 10.1093/oxfordjournals.aje.a121228

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 1971

detail.hit.zdb_id: 2030043-8

In: Journal of Neuroscience Research, Wiley, Vol. 76, No. 1 ( 2004-04), p. 129-140

Abstract: Although the phenotypic and regulatory properties of the CD4 + CD25 + T cell lineage (Treg cells) have been well described, the specificities remain largely unknown. We demonstrate here that the CD4 + CD25 + Treg population includes the recognition of a broad spectrum of human TCR CDR2 determinants found in the germline V gene repertoire as well as that of a clonotypic nongermline‐encoded CDR3β sequence present in a recombinant soluble T cell receptor (TCR) protein. Regulatory activity was demonstrated in T cell lines responsive to TCR but not in T cell lines responsive to control antigens. Inhibitory activity of TCR‐reactive T cells required cell–cell contact and involved CTLA‐4, GITR, IL‐10, and IL‐17. Thus, the T–T regulatory network includes Treg cells with specificity directed toward self‐TCR determinants. © 2004 Wiley‐Liss, Inc.

Type of Medium: Online Resource

ISSN: 0360-4012 , 1097-4547

URL: Issue

URL: Article

DOI: 10.1002/jnr.v76:1

DOI: 10.1002/jnr.20066

Language: English

Publisher: Wiley

Publication Date: 2004

detail.hit.zdb_id: 1474904-X

SSG: 12

In: American Journal of Medical Genetics, Wiley, Vol. 45, No. 5 ( 1993-03-01), p. 577-580

Type of Medium: Online Resource

ISSN: 0148-7299 , 1096-8628

URL: Issue

URL: Journal

URL: Article

DOI: 10.1002/ajmg.v45:5

DOI: 10.1002/(ISSN)1096-8628

DOI: 10.1002/ajmg.1320450511

Language: English

Publisher: Wiley

Publication Date: 1993

detail.hit.zdb_id: 2143866-3

detail.hit.zdb_id: 2143867-5

detail.hit.zdb_id: 1493479-6

detail.hit.zdb_id: 2205916-7

SSG: 12

In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2855-2855

Abstract: Background: Treatment of metastatic, castrate-resistant prostate cancer (CRPC) remains a highly unmet medical need. We have developed a bispecific SCORPIONTM (multi-specific protein therapeutic) molecule that redirects T cell cytotoxicity against cells expressing PSMA (Prostate Specific Membrane Antigen), a common prostate-cancer related antigen. The SCORPION molecule described here contains two pairs of binding domains, each targeting a unique antigen, linked to opposite ends of an immunoglobulin Fc domain to extend the half-life of the molecule in vivo. In these studies, we examine the ability of a SCORPION molecule targeting both CD3 and PSMA, to inhibit the growth of PSMA expressing tumors in vivo. Materials and Methods: NOD/SCID mice were implanted with the PSMA(+) prostate tumor cell line C4-2B and purified human T cells in one of two models. In a first model of residual disease, C4-2B cells were coimplanted subcutaneously with human T cells, and treatment with drug was initiated immediately. This model was run twice with T cells from two different human donors. In a second model of established disease, C4-2B cells were implanted subcutaneously and allowed to develop for 20 days, after which human T cells were injected intra-peritoneally, with subsequent administration of drug. Tumor growth was assessed by tumor volume and serum PSA, and tumor volume and weight loss were used as endpoints. Results: SCORPION molecules targeting PSMA and CD3 inhibited growth of PSMA(+) tumors in both model settings and significantly improved overall survival. Reduction in circulating serum PSA was also observed. Repeat studies using a second human T cell donor showed similar inhibition of tumor growth and overall survival. Inhibition of tumor growth was seen at doses in the low pmol range per mouse. Conclusions: These studies show that anti-PSMA x anti-CD3 SCORPION therapeutics redirect T cell cytotoxicity in in vivo xenograft models and merit further investigation as potential therapeutics in CRPC. Citation Format: Robert Miller, Hang Fang, Jessica Luke, Megan Aguilar, Ruth Chenault, John Kumer, Jennifer Wiens, Paul Algate, David Bienvenue, Catherine McMahan, Holly Nguyen, Robert Vessella, John Blankenship. Anti-PSMA x anti-CD3 SCORPIONTM molecule inhibits tumor growth in vivo in mouse models of prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2855. doi:10.1158/1538-7445.AM2013-2855

Type of Medium: Online Resource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/1538-7445.AM2013-2855

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2013

detail.hit.zdb_id: 2036785-5

detail.hit.zdb_id: 1432-1

detail.hit.zdb_id: 410466-3

In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. LB173-LB173

Abstract: APVO603 is Aptevo's bispecific candidate targeting 4-1BB and OX40. It was designed to have unique properties with the potential to overcome some of the clinical challenges observed with monoclonal antibody targeting these receptors. APVO603 is engineered as an FcγR-signaling deficient bispecific antibody that utilizes Aptevo's ADAPTIR technology for a distinct approach for dual targeting of 4-1BB and OX40 in the absence of additional effector activity. The distinct characteristics of APVO603 may enable conditional activation of 4-1BB and OX40 via agonism of these receptors only when cross-linked via engagement of the other receptor via cis and/or trans cellular interactions. Thus, APVO603 is designed with the potential to overcome both the on-target toxicity and limited efficacy observed with 4-1BB and OX40 monoclonal antibody treatment in the clinic. Anti-4-1BB and OX40 binding domains were optimized to increase affinity, function and stability, then incorporated into the ADAPTIR bispecific antibody platform to produce the APVO603 lead candidate. APVO603 was found to augment 4-1BB and OX40 activity in a dose-dependent manner and is strictly dependent on engagement of the reciprocal receptor to elicit 4-1BB or OX40 signaling in vitro. In preclinical assays using PBMCs sub-optimally stimulated with anti-CD3, APVO603 induces synergistic proliferation of CD4+, CD8+ T and NK cells when compared to anti-OX40 or 4-1BB antibodies with a wt Fc, included either individually or in combination. Additionally, APVO603 enhances proinflammatory cytokine production, granzyme B expression, and reduces the T cell exhaustion phenotype. The mechanistic activity of APVO603 resulted in dose-dependent control of in vivo tumor growth in a preclinical humanized murine xenograft model using established murine MB49 bladder tumors in human 4-1BB and OX40 double knock-in mice. APVO603 is a dual-agonistic bispecific antibody that augments the effector function of activated CD4+ and CD8+ T cells and NK cells in a dose-dependent manner and reduces growth of established tumors in vivo. This preclinical data demonstrates conditional dual stimulation of 4-1BB and OX40 and supports further development of APVO603, a promising immuno-oncology therapeutic with potential for benefit in solid tumors. This program is progressing into IND-enabling studies later this year. Citation Format: Michelle H. Nelson, Robert E. Miller, Secil Franke-Welch, Ruth Chenault, Hang Fang, Allison Chunyk, Gabriela Hernandez-Hoyos, Hilario J. Ramos, David Bienvenue, Catherine McMahan. APVO603: A dual 4-1BB and OX40 bispecific approach utilizing ADAPTIRTMtechnology designed to deliver a conditional T cell/NK response against solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB173.

Type of Medium: Online Resource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/1538-7445.AM2021-LB173

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2021

detail.hit.zdb_id: 2036785-5

detail.hit.zdb_id: 1432-1

detail.hit.zdb_id: 410466-3

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3722-3722

Abstract: Abstract 3722 Background: Despite advances in treatments for B-cell leukemias and lymphomas, many patients ultimately relapse and succumb to disease following multiple courses of therapy. Bispecific antibody fragments that can simultaneously engage T cells and tumor cells have been shown, in the literature, to destroy tumor cells by effectively redirecting the cytotoxic function of T cells. T-cell engaging bispecific molecules linking anti-CD19 and anti-CD3 binding domains in the context of novel SCORPION™ (multi-specific protein therapeutic) proteins were evaluated both in vitro and in vivo for function and stability. Methods: Redirected T-cell cytotoxicity (RTCC) was measured by combining CD19 positive or negative cell lines with SCORPION proteins in the presence of human T cells. In a similar assay context, CFSE-labeled T cells were monitored for activation and proliferation. Functional RTCC assays were also used to analyze serum stability of SCORPION molecules in vitro and to complete an in vivo pharmacokinetic analysis. In vivo efficacy was assessed by monitoring the rate of tumor outgrowth of Ramos xenografts co-implanted with human peripheral blood mononuclear cells (PBMC) in NOD/SCID mice after treatment with SCORPION molecules. Results: SCORPION molecules potently mediate target-specific T-cell cytotoxicity toward tumor cell lines presenting cell surface CD19, with EC50 values for cytotoxicity at low pM concentrations. These molecules also demonstrate induction of T-cell activation and proliferation in the presence of target-bearing tumor cells but not in the absence of target expression. SCORPION molecules retain stable function following incubation at 37°C in mouse serum for up to a week in vitro, and pharmacokinetic analysis of SCORPION protein function in BALB/c mouse serum following intravenous administration resulted in half-life estimates of 69–84 hours. In efficacy studies conducted in NOD/SCID mice, SCORPION proteins significantly inhibited the outgrowth of Ramos tumor xenografts in the presence of human effector cells. Conclusion: SCORPION molecules targeting CD19 and CD3 effectively harness the cytotoxic activity of T cells to kill CD19 positive tumor cells both in vitro and in vivo and show potential for further investigation as possible therapeutic agents for B-cell malignancies. Disclosures: Chenault: Emergent BioSolutions: Employment. Gottschalk:Emergent BioSolutions: Employment. Hernandez-Hoyos:Emergent BioSolutions: Employment. Wiens:Emergent BioSolutions: Employment. Gordon:Emergent BioSolutions: Employment. Klee:Emergent BioSolutions: Employment, Equity Ownership. Bienvenue:Emergent BioSolutions: Employment. Dasovich:Emergent BioSolutions: Employment. Kumer:Emergent BioSolutions: Employment. Aguilar:Emergent BioSolutions: Employment. Bannink:Emergent BioSolutions: Employment, Equity Ownership. McMahan:Emergent BioSolutions: Employment, Equity Ownership. Natarajan:Emergent BioSolutions: Employment, Equity Ownership. Algate:Emergent BioSolutions: Employment, Equity Ownership. Blankenship:Emergent BioSolutions: Employment, Equity Ownership, Patents & Royalties.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.3722.3722

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 11-12

Abstract: Introduction Immunotherapy offers the promise of a new paradigm for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). CD123, the IL-3 receptor alpha-chain, represents an attractive target for antibody therapies because of its high expression on AML/MDS blasts and leukemic stem cells compared to normal hematopoietic stem and progenitor cells. APVO436, a novel bispecific anti-CD123 x anti-CD3 ADAPTIR™ molecule, depleted CD123+ cells in AML patient samples ex vivo (Godwin et al. ASH 2017), reduced leukemia engraftment in a systemic AML xenograft model (Comeau et al. AACR 2018), and transiently reduced peripheral CD123+ cells in non-human primates with minimal cytokine release and in a dose-dependent fashion (Comeau et al. AACR 2019). These data provide a basis for the clinical application of APVO436 as a treatment in AML and MDS. Here, we report preliminary data from a first-in-human dose-escalation study of APVO436 in patients with R/R AML and high-risk MDS. Study Design/Methods This ongoing Phase 1/1b study (ClinicalTrials.gov: NCT03647800) was initiated to determine the safety, immunogenicity, pharmacokinetics, pharmacodynamics, and clinical activity of APVO436 as a single agent. Major inclusion criteria were: R/R AML with no other standard treatment option available, R/R MDS with & gt; 5% marrow blasts or any peripheral blasts and failure of a hypomethylating agent, ECOG performance status ≤ 2, life expectancy & gt; 2 months, white blood cells ≤ 25,000 cells/mm3, creatinine ≤ 2 x upper limit of normal (ULN), INR and PTT & lt; 1.5 x ULN and alanine aminotransferase & lt; 3 x ULN. Patients were not restricted from treatment due to cytogenetic or mutational status. Intravenous doses of APVO436 were administered weekly for up to six 28-day cycles (24 doses) with the option to continue dosing for up to 36 total cycles (144 doses). Flat and step dosing regimens were escalated using a safety-driven modified 3 + 3 design. Pre-medication with diphenhydramine, acetaminophen, and dexamethasone was administered starting with dose 1 to mitigate infusion related reactions (IRR) and cytokine release syndrome (CRS). First doses and increasing step doses of APVO436 were infused over 20-24 hours followed by an observation period of 24 hours or more. Bone marrow biopsies were performed every other cycle with responses assessed by European Leukemia Net 2017 criteria for AML or International Working Group (IWG) 2006 criteria for MDS. Results The data cut-off for this interim analysis was July 9, 2020. Twenty-eight patients with primary R/R AML (n=19), therapy-related R/R AML (n=3), or high-risk MDS (n=6) have been enrolled and received a cumulative total of 186 doses. The number of doses received per patient ranged from 1 to 43 (mean of 6.4 doses). Most patients discontinued treatment due to progressive disease; however, blast reduction was achieved in 2 patients, with one patient with MDS maintaining a durable response for 11 cycles before progressing. APVO436 was tolerated across all dose regimens in all cohorts tested. The most common adverse events (AEs), regardless of causality, were edema (32%), diarrhea (29%), febrile neutropenia (29%), fever (25%), hypokalemia (25%), IRR (21%), CRS (18%), chills (18%), and fatigue (18%). AEs ≥ Grade 3 occurring in more than one patient were: febrile neutropenia (25%), anemia (18%), hyperglycemia (14%), decreased platelet count (11%), CRS (11%), IRR (7%), and hypertension (7%). After observing a single dose limiting toxicity (DLT) at a flat dose of 9 µg, step dosing was implemented and no DLTs have been observed thereafter. No treatment-related anti-drug antibodies (ADA) were observed. Transient serum cytokine elevations occurred after several reported IRR and CRS events, with IL-6 most consistently elevated. Conclusions Preliminary results indicate that APVO436 is tolerated in patients with R/R AML and MDS at the doses and schedules tested to date, with a manageable safety profile. Dose escalation continues and the results will be updated for this ongoing study. Disclosures Watts: BMS: Membership on an entity's Board of Directors or advisory committees; Aptevo Therapeutics: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Lin:Ono Pharmaceutical: Research Funding; Pfizer: Research Funding; Abbvie: Research Funding; Bio-Path Holdings: Research Funding; Astellas Pharma: Research Funding; Aptevo: Research Funding; Celgene: Research Funding; Genetech-Roche: Research Funding; Celyad: Research Funding; Prescient Therapeutics: Research Funding; Seattle Genetics: Research Funding; Mateon Therapeutics: Research Funding; Jazz: Research Funding; Incyte: Research Funding; Gilead Sciences: Research Funding; Trovagene: Research Funding; Tolero Pharmaceuticals: Research Funding. Wang:Abbvie: Consultancy; Macrogenics: Consultancy; Astellas: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; PTC Therapeutics: Consultancy; Stemline: Speakers Bureau; Genentech: Consultancy; Pfizer: Speakers Bureau. Mims:Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Agios: Consultancy; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board; Abbvie: Membership on an entity's Board of Directors or advisory committees. Cull:Aptevo Therapeutics: Research Funding. Patel:Agios: Consultancy; Celgene: Consultancy, Speakers Bureau; DAVA Pharmaceuticals: Honoraria; France Foundation: Honoraria. Shami:Aptevo Therapeutics: Research Funding. Walter:Aptevo Therapeutics: Research Funding. Cogle:Aptevo Therapeutics: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Chenault:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Macpherson:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Chunyk:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. McMahan:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gross:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Stromatt:Aptevo Therapeutics: Current equity holder in publicly-traded company.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-141619

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Atherosclerosis, Elsevier BV, Vol. 37, No. 1 ( 1980-9), p. 103-121

Type of Medium: Online Resource

ISSN: 0021-9150

URL: Article

DOI: 10.1016/0021-9150(80)90098-2

Language: English

Publisher: Elsevier BV

Publication Date: 1980

detail.hit.zdb_id: 1499887-7

In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 15, No. 9 ( 2016-09-01), p. 2155-2165

Abstract: Treatment of metastatic, castration-resistant prostate cancer (mCRPC) remains a highly unmet medical need and current therapies ultimately result in disease progression. Immunotherapy is a rapidly growing approach for treatment of cancer but has shown limited success to date in the treatment of mCRPC. We have developed a novel humanized bispecific antibody, MOR209/ES414, built on the ADAPTIR (modular protein technology) platform, to redirect T-cell cytotoxicity toward prostate cancer cells by specifically targeting T cells through CD3ϵ to prostate cancer cells expressing PSMA (prostate-specific membrane antigen). In vitro cross-linking of T cells with PSMA-expressing tumor cells by MOR209/ES414 triggered potent target-dependent tumor lysis and induction of target-dependent T-cell activation and proliferation. This activity occurred at low picomolar concentrations of MOR209/ES414 and was effective at low T-effector to tumor target cell ratios. In addition, cytotoxic activity was equivalent over a wide range of PSMA expression on target cells, suggesting that as few as 3,700 PSMA receptors per cell are sufficient for tumor lysis. In addition to high sensitivity and in vitro activity, MOR209/ES414 induced limited production of cytokines compared with other bispecific antibody formats. Pharmacokinetic analysis of MOR209/ES414 demonstrated a serum elimination half-life in NOD/SCID γ (NSG) mice of 4 days. Administration of MOR209/ES414 in murine xenograft models of human prostate cancer significantly inhibited tumor growth, prolonged survival, and decreased serum prostate-specific antigen levels only in the presence of adoptively transferred human T cells. On the basis of these preclinical findings, MOR209/ES414 warrants further investigation as a potential therapeutic for the treatment of CRPC. Mol Cancer Ther; 15(9); 2155–65. ©2016 AACR.

Type of Medium: Online Resource

ISSN: 1535-7163 , 1538-8514

URL: Article

DOI: 10.1158/1535-7163.MCT-15-0242

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2016

detail.hit.zdb_id: 2062135-8

SSG: 12

In: New England Journal of Medicine, Massachusetts Medical Society, Vol. 275, No. 3 ( 1966-07-21), p. 131-136

Type of Medium: Online Resource

ISSN: 0028-4793 , 1533-4406

URL: Article

DOI: 10.1056/NEJM196607212750303

Language: English

Publisher: Massachusetts Medical Society

Publication Date: 1966

detail.hit.zdb_id: 1468837-2