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Breij E.C.W.,Genmab | De Goeij B.E.C.G.,Genmab | Verploegen S.,Genmab | Schuurhuis D.H.,Genmab | And 7 more authors.
Cancer Research | Year: 2014

Tissue factor (TF) is aberrantly expressed in solid cancers and is thought to contribute to disease progression through its procoagulant activity and its capacity to induce intracellular signaling in complex with factor VIIa (FVIIa). To explore the possibility of using tissue factor as a target for an antibody-drug conjugate (ADC), a panel of human tissue factor-specific antibodies (TF HuMab) was generated. Three tissue factor HuMab, that induced efficient inhibition of TF:FVIIa-dependent intracellular signaling, antibodydependent cell-mediated cytotoxicity, and rapid target internalization, but had minimal impact on tissue factor procoagulant activity in vitro, were conjugated with the cytotoxic agents monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF). Tissue factor-specific ADCs showed potent cytotoxicity in vitro and in vivo, which was dependent on tissue factor expression. TF-011-MMAE (HuMax-TF-ADC) was the most potent ADC, and the dominant mechanism of action in vivo was auristatin-mediated tumor cell killing. Importantly, TF-011-MMAE showed excellent antitumor activity in patient-derived xenograft (PDX) models with variable levels of tissue factor expression, derived from seven different solid cancers. Complete tumor regression was observed in all PDX models, including models that showed tissue factor expression in only 25% to 50% of the tumor cells. In conclusion, TF-011-MMAE is a promising novel antitumor agent with potent activity in xenograft models that represent the heterogeneity of human tumors, including heterogeneous target expression. © 2014 American Association for Cancer Research.


Gil-Bernabe A.M.,University of Oxford | Ferjancic S.,University of Oxford | Tlalka M.,University of Oxford | Zhao L.,University of Oxford | And 9 more authors.
Blood | Year: 2012

Tissue factor (TF) expression by tumor cells correlates with metastasis clinically and supports metastasis in experimental settings. However, the precise pathways coupling TF to malignancy remain incompletely defined. Here, we show that clot formation by TF indirectly enhances tumor cell survival after arrest in the lung, during experimental lung metastasis, by recruiting macrophages characterized by CD11b, CD68, F4/80, and CX3CR1 (but not CD11c) expression. Genetic or pharmacologic inhibition of coagulation, by either induction of TF pathway inhibitor expression or by treatment with hirudin, respectively, abrogated macrophage recruitment and tumor cell survival. Furthermore, impairment of macrophage function, in either Mac1-deficient mice or in CD11b-diphtheria toxin receptor mice in which CD11b-positive cells were ablated, decreased tumor cell survival without altering clot formation, demonstrating that the recruitment of functional macrophages was essential for tumor cell survival. This effect was independent of NK cells. Moreover, a similar population of macrophages was also recruited to the lung during the formation of a premetastatic niche. Anticoagulation inhibited their accumulation and prevented the enhanced metastasis associated with the formation of the niche. Our study, for the first time, links TF induced coagulation to macrophage recruitment in the metastatic process. © 2012 by The American Society of Hematology.


Robles-Carrillo L.,Center for Thrombosis Research | Meyer T.,Center for Thrombosis Research | Hatfield M.,Center for Thrombosis Research | Desai H.,Center for Thrombosis Research | And 7 more authors.
Journal of Immunology | Year: 2010

Anti-CD40L immunotherapy in systemic lupus erythematosus patients was associated with thromboembolism of unknown cause. We previously showed that monoclonal anti-CD40L immune complexes (ICs) activated platelets in vitro via the IgG receptor (FcγRIIa). In this study, we examined the prothrombotic effects of anti-CD40L ICs in vivo. Because mouse platelets lack FcγRIIa, we used FCGR2A transgenic mice. FCGR2A mice were injected i.v. with preformed ICs consisting of either anti-human CD40L mAb (M90) plus human CD40L, or a chimerized anti-mouse CD40L mAb (hMR1) plus mouse CD40L. ICs containing an aglycosylated form of hMR1, which does not bind FcγRIIa, were also injected. M90 IC caused shock and thrombocytopenia in FCGR2A but not in wild-type mice. Animals injected with hMR1 IC also experienced these effects, whereas those injected with aglycosylated-hMR1 IC did not, demonstrating that anti-CD40L IC-induced platelet activation in vivo is FcγRIIa-dependent. Sequential injections of individual IC components caused similar effects, suggesting that ICs were able to assemble in circulation. Analysis of IC-injected mice revealed pulmonary thrombi consisting of platelet aggregates and fibrin. Mice pretreated with a thrombin inhibitor became moderately thrombocytopenic in response to anti-CD40L ICs and had pulmonary platelet-thrombi devoid of fibrin. In conclusion, we have shown for the first time that anti-CD40L IC-induced thrombosis can be replicated in mice transgenic for FcγRIIa. This molecular mechanism may be important for understanding thrombosis associated with CD40L immunotherapy. The FCGR2A mouse model may also be useful for assessing the hemostatic safety of other therapeutic Abs. Copyright © 2010 by The American Association of Immunologists, Inc.


Shock A.,UCB Pharma | Burkly L.,Biogen Idec | Wakefield I.,UCB Pharma | Peters C.,UCB Pharma | And 22 more authors.
Arthritis Research and Therapy | Year: 2015

Introduction: CD40 ligand (CD40L) blockade has demonstrated efficacy in experimental autoimmune models. However, clinical trials of hu5c8, an anti-human CD40L IgG1 antibody, in systemic lupus erythematosus (SLE) were halted due to an increased incidence of thrombotic events. This study evaluated CDP7657, a high affinity PEGylated monovalent Fab' anti-CD40L antibody fragment, to assess whether an Fc-deficient molecule retains efficacy while avoiding the increased risk of thrombotic events observed with hu5c8. Methods: The potency and cross-reactivity of CDP7657 was assessed in in vitro assays employing human and non-human primate leukocytes, and the capacity of different antibody formats to activate platelets in vitro was assessed using aggregometry and dense granule release assays. Given the important role CD40L plays in regulating humoral immunity, in vivo efficacy was assessed by investigating the capacity of Cynomolgus monkeys to generate immune responses to the tetanus toxoid antigen while the potential to induce thrombotic events in vivo was evaluated after repeat dosing of antibodies to Rhesus monkeys. A PEGylated anti-mouse CD40L was generated to assess efficacy in the New Zealand Black/White (NZB/W) mouse model of SLE. Results: CDP7657 dose-dependently inhibited antigen-specific immune responses to tetanus toxoid in Cynomolgus monkeys, and in contrast to hu5c8, there was no evidence of pulmonary thrombovasculopathy in Rhesus monkeys. Aglycosyl hu5c8, which lacks Fc receptor binding function, also failed to induce thrombotic events in Rhesus monkeys. In vitro experiments confirmed that antibody constructs lacking an Fc, including CDP7657, did not induce human or monkey platelet activation. A PEGylated monovalent Fab' anti-mouse CD40L antibody also inhibited disease activity in the NZB/W mouse model of SLE after administration using a therapeutic dosing regimen where mice received antibodies only after they had displayed severe proteinuria. Conclusions: These findings demonstrate for the first time that anti-CD40L antibodies lacking a functional Fc region do not induce thrombotic events in Rhesus monkeys and fail to activate platelets in vitro but, nevertheless retain pharmacological activity and support the investigation of CDP7657 as a potential therapy for systemic lupus erythematosus and other autoimmune diseases. © 2015 Shock et al.


Navarese E.P.,Nicolaus Copernicus University | Gurbel P.A.,Center for Thrombosis Research | Andreotti F.,Catholic University | Tantry U.,Center for Thrombosis Research | And 9 more authors.
Annals of Internal Medicine | Year: 2013

Background: The optimal timing of coronary intervention in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACSs) is a matter of debate. Conflicting results among published studies partly relate to different risk profiles of the studied populations. Purpose: To do the most comprehensive meta-analysis of current evidence on early versus delayed invasive treatment in NSTE-ACS. Data Sources: MEDLINE, PubMed Central, and Google Scholar databases; conference proceedings; ClinicalTrials.gov registry; and Current Controlled Trials registry through May 2012. Study Selection: Available randomized, controlled trials (RCTs) and observational studies comparing early versus delayed intervention in the NSTE-ACS population. Data Extraction: Data were extracted for populations, interventions, outcomes, and risk of bias. All-cause mortality was the prespecified primary end point. The longest follow-up available in each study was chosen. The odds ratio with 95% CI was the effect measure. Data Synthesis: Seven RCTs (5370 patients) and 4 observational studies (77 499 patients) were included. Early intervention was less than 20 hours after hospitalization or randomization for RCTs and 24 hours or less for observational studies. Meta-analysis of the RCTs was inconclusive for a survival benefit associated with the early invasive strategy (odds ratio, 0.83 [95% CI, 0.64 to 1.09]; P = 0.180); a similar result emerged from the observational studies. With early versus late intervention, the odds ratios in the RCTs were 1.15 (CI, 0.65 to 2.01; P = 0.63) and 0.76 (CI, 0.56 to 1.04; P = 0.090) for myocardial infarction and major bleeding during follow-up, respectively. Limitation: Current evidence from RCTs is limited by the small overall sample size, low numbers of events in some trials, and heterogeneity in the timing of intervention and in patient risk profiles. Conclusion: At present, there is insufficient evidence either in favor of or against an early invasive approach in the NSTE-ACS population. A more definitive RCT is warranted to guide clinical practice. Primary Funding Source: None. © 2013 American College of Physicians.

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