Otlertuzumab is a novel humanized anti-CD37 protein therapeutic. This study evaluated the safety of otlertuzumab administered intravenously to patients with chronic lymphocytic leukemia (CLL). ...Otlertuzumab was administered weekly for up to 8 weeks followed by 1 dose per month for 4 months ranging from 0.03 to 20 mg/kg in the dose-escalation phase and 10 to 30 mg/kg in the dose-expansion phase. Responses were determined by using the 1996 National Cancer Institute (NCI-96) and 2008 International Workshop on Chronic Lymphocytic Leukaemia (IWCLL) criteria. Fifty-seven patients were treated in the dose-escalation phase and 26 in the dose-expansion phase. A maximum-tolerated dose was not identified. Response occurred in 19 (23%) of 83 treated patients by NCI-96 criteria. All responses were partial and occurred more commonly in patients with symptomatic untreated CLL (6/7) or 1 to 2 prior therapies (12/28) vs 3 or more therapies (1/48). Twenty percent (12/61) with serial computed tomography scan assessment had a response per IWCLL criteria. The most frequent adverse events were infusion reactions, fatigue, nausea, and diarrhea and were not dose related. Otlertuzumab was well tolerated, and modest clinical activity was observed. Otlertuzumab warrants further evaluation in combination with other agents for the treatment of CLL. This trial was registered at www.clinicaltrials.gov as #NCT00614042.
•Otlertuzumab (formerly TRU-016) has modest single-agent activity in symptomatic treated and untreated CLL.•Otlertuzumab demonstrates an acceptable safety profile, providing rationale for combination with other effective CLL therapies.
Monoclonal antibodies have begun to show great clinical promise for the treatment of cancer. Antibodies that can directly affect a tumor cell's growth and/or survival are of particular interest for ...immunotherapy. Previously, we described monoclonal antibody DMF10.62.3 that had antiproliferative and proapoptotic effects when it bound an antigen of unknown identity on tumor cells in vitro. In this report, we determined that DMF10.62.3 and a clonally related antibody DMF10.167.4 recognize the ganglioside GM2. These antibodies react with a GM2 epitope that is expressed on a large number of tumor cell lines, including human melanoma and small cell lung carcinoma, but not on normal primary lines or most normal tissues. Interestingly, this pattern of cellular reactivity is distinct from that reported for other previously described GM2 antibodies, a difference that is presumably due to DMF10.167.4's binding to a unique GM2-associated epitope. Additional characterization of DMF10.167.4 revealed that this antibody was able to induce apoptosis and/or block cellular proliferation when cultured in vitro with the human Jurkat T lymphoma, CHL-1 melanoma, and SBC-3 small cell lung carcinoma lines. In vivo, DMF10.167.4 antibody was well tolerated in mice and did not detectably bind to or damage normal tissues. However, this antibody was able to prevent murine E710.2.3 lymphoma, human CHL-1 melanoma, and SBC-3 small cell lung carcinoma lines from establishing tumors in vivo and blocked progression of established CHL-1 and SBC-3 tumors in vivo. Therefore, monoclonal antibody DMF10.167.4 has immunotherapeutic potential.
Abstract 3722
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.
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.
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.
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.
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.
Abstract Background : TRU-015 is a small modular immunopharmaceutical protein drug that binds to CD20 and effectively depleted B cells in nonhuman primates. Objective : The aim of this clinical study ...was to determine the pharmacokinetic (PK) and pharmacodynamic (PD) properties, immunogenicity, and tolerability of TRU-015 in patients with rheumatoid arthritis (RA). Methods : This Phase I, open-label, dose-escalation clinical study was conducted at 4 medical centers in the United States. Patients with RA who were receiving stable-dose methotrexate were enrolled in 1 of 8 dose groups and received TRU-015 as a single IV dose of 0.015, 0.05, 0.15, 0.5, 1.5, 5, or 15, or 2 IV doses of 15 mg/kg, administered 7 days apart (30 mg/kg). Patients were enrolled in the next higher dose cohort based on the tolerability observed in the prior cohort. Prior to TRU-015 infusion, patients were premedicated with an antihistamine and acetaminophen and may have received a corticosteroid at the investigator's discretion. Serum samples were collected for analysis of PK properties (serum t½ ) and neutralizing antibodies to TRU-015; enzyme-linked immunosorbent assays and a cell-based neutralizing assay were used to evaluate samples from patients. PD response was measured using B-cell (CD19+ -cell) count using flow cytometry at prespecified time points. Tolerability was assessed during drug infusion and at prespecified time points after infusion using physical examination and laboratory analysis. Patients were followed for ≥4 weeks and until B-cell recovery. Results : Thirty-seven patients were enrolled. Most were female (81%) and white (95%); the mean age was 53 years. Serum t½ ranged from 12 to 19 days. B-cell depletion generally increased in degree and duration with increasing doses. No neutralizing antibodies to TRU-015 were detected. Mild adverse events (AEs) included back pain, headache, peripheral edema, and upper respiratory infection (5 patients each). Mild urticaria occurred in 1 patient. Grade 3 AEs included hypertension, arthralgia, and urticaria and bronchospasm (1 patient each). No dose-limiting toxicity was found. Conclusions : In this small population of patients with RA, the Cmax and the AUC appeared to increase in a dose-proportional manner. The mean t½ ranged from 12 to 19 days. TRU-015 was associated with dose-dependent B-cell depletion and an acceptable tolerability profile.
The present study utilizes an in vivo murine tumor expressing human Her-2/neu to evaluate potential Her-2/neu vaccines consisting of either full length or various subunits of Her-2/neu delivered in ...either protein or plasmid DNA form. Our results demonstrate that protective immunity against Her-2/neu-expressing tumor challenge can be achieved by vaccination with plasmid DNA encoding either full length or subunits of Her-2/neu. Partial protective immunity was also observed following vaccination with the intracellular domain (ICD), but not extracellular domain (ECD), protein subunit of Her-2/neu. The mechanism of protection elicited by plasmid DNA vaccination appeared to be exclusively CD4 dependent, whereas the protection observed with ICD protein vaccination required both CD4 and CD8 T cells.
With few exceptions, humans are the only species known to develop acquired immunodeficiency syndrome (AIDS) after human immunodeficiency virus (HIV) infection. We report here that an isolate of HIV ...type 2, EHO, readily established persistent infection in 100% of Macaca
nemestrina in three consecutive transmission studies. Of the eight
infected animals, five showed persistently high virus load and six
developed AIDS‐like diseases or CD4+ cell depletion within 4
years of infection. The pathology and clinical signs closely parallel
those of HIV‐1 infection of humans, including lymphadenopathy, anemia,
CD4+ cell depletion, and opportunistic infections. A cell‐free
virus stock was established from the lymph nodes of an animal that
developed AIDS‐like diseases. This virus, HIV‐2/287, was highly
pathogenic in M. nemestrina, causing CD4+ cell
depletion within 2–8 weeks post‐infection. While both HIV‐2 EHO and
HIV‐2/287 use predominantly CXCR4, the latter shows greatly enhanced
replicative capacity in macaque peripheral blood mononuclear cells
(PBMCs). The establishment of a human immunodeficiency virus that causes
rapid and reproducible CD4+ cell depletion in macaques could facilitate the study of HIV pathogenesis and the development of effective vaccines and therapy against AIDS.
The rapid introduction of technical innovations in healthcare requires that professionals are adequately prepared for correct clinical use of medical technology. In response to the technological ...transformation of healthcare, a new type of professional, the Technical Physician (TP), was created and is trained to improve individual patient care using technology tailored to the needs of individual patients. This study investigates the TPs' impact on patient care in terms of innovation, effectiveness, efficiency, and patient safety.
Semi-structured, in-depth interviews were conducted with 30 TPs and 17 medical specialists (MSs) working in academic or teaching hospitals in the Netherlands. The pre-structured and open-ended interview questions focused on: 1) the perceived impact on innovation, effectiveness, efficiency, and safety, and 2) opportunities and challenges in daily work.
TPs and MSs unanimously experienced that TPs contributed to innovation. A majority indicated that effectiveness (TP 57%; MS 71%) and efficiency (TP 67%; MS 65%) of clinical practice had increased. For safety, 87% of TPs but only 47% of MSs reported an increase. The main explanation given for TPs positive impact was combining medical and technical knowledge. Mainly organizational barriers were mentioned as a potential cause for a less visible contribution of TPs.
TPs and MSs unanimously agreed that TPs contributed to innovating patient care through their integrative medical and technical competencies. Most TPs and MSs also reported increased effectiveness, efficiency, and safety of patient care due to the TPs' work. TPs and MSs expected that the TPs' impact on direct and indirect patient care will be enhanced once organizational barriers are removed.
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