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Iqbal S. Grewal - One of the best experts on this subject based on the ideXlab platform.

  • Selective recruitment of γδ T cells by a Bispecific Antibody for the treatment of acute myeloid leukemia
    Leukemia, 2021
    Co-Authors: Rajkumar Ganesan, Vijaykumar Chennupati, Balaji Ramachandran, Michael Riis Hansen, Sanjaya Singh, Iqbal S. Grewal
    Abstract:

    Despite significant progress over the last few decades in the treatment of acute myeloid leukemia (AML), there still remains a major unmet medical need for this disease. Immunotherapy approaches for redirecting pan CD3^+ T cells to target leukemia blasts have shown limited efficacy in clinical trials and often accompanied with severe toxicity in AML patients. We designed an alternative engager molecule (Anti-TRGV9/anti-CD123), a Bispecific Antibody that can simultaneously bind to the Vγ9 chain of the Vγ9Vδ2^+ γδ T cell receptor and to AML target antigen, CD123, to selectively recruit Vγ9^+ γδ T cells rather than pan T cells to target AML blasts. Our results suggest that prototypic Bispecific antibodies (a) selectively activate Vγ9^+ γδ T cells as judged by CD69 and CD25 surface expression, and intracellular Granzyme B expression, (b) selectively recruit Vγ9^+ γδ T cells into cell–cell conjugate formation of γδ T cells with tumor cells indicating selective and effective engagement of effector and target tumor cells, and (c) mediate γδ T cell cytotoxicity (in vitro and in vivo) against tumor antigen-expressing cells. Collectively, these findings suggest that selectively redirecting Vγ9^+ γδ T cells to target AML blasts has a potential for immunotherapy for AML patients and favors further exploration of this concept.

  • Bispecific Antibodies for Triple Negative Breast Cancer
    Trends in cancer, 2020
    Co-Authors: Sundee Dees, Rajkumar Ganesan, Sanjaya Singh, Iqbal S. Grewal
    Abstract:

    Triple negative breast cancer (TNBC), an aggressive breast cancer subtype lacking estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression, is associated with heightened metastatic potential and poor prognosis. While systemic chemotherapy, radiation, and surgical excision remain the current treatment modalities for patients with TNBC, the immunogenic nature of this aggressive disease has presented opportunity for the development of TNBC-targeting immunotherapies. Bispecific Antibody-based therapeutics for the treatment of TNBC have gained recent attention in the scientific community. Clinical precedent has been previously established for the FDA-approved Bispecific T cell engager, blinatumomab, for acute lymphoblastic leukemia. The present review discusses novel Bispecific antibodies for TNBC and emerging TNBC targets for future Bispecific Antibody development.

Brigitte Kerfelec - One of the best experts on this subject based on the ideXlab platform.

  • A Bispecific Antibody-Based Approach for Targeting Mesothelin in Triple Negative Breast Cancer
    Frontiers in Immunology, 2019
    Co-Authors: Joanie Del Bano, Rémy Florès-florès, Emmanuelle Josselin, Armelle Goubard, Laëtitia Ganier, Rémy Castellano, Patrick Chames, Daniel Baty, Brigitte Kerfelec
    Abstract:

    Triple negative breast cancers (TNBC) remain a major medical challenge due to poor prognosis and limited treatment options. Mesothelin is a glycosyl-phosphatidyl inositol-linked membrane protein with restricted normal expression and high level expression in a large proportion of TNBC, thus qualifying as an attractive target. Its overexpression in breast tumors has been recently correlated with a decreased disease-free survival and an increase of distant metastases. The objective of the study was to investigate the relevance of a Bispecific Antibody-based immunotherapy approach through mesothelin targeting and CD16 engagement using a Fab-like Bispecific format (MesobsFab). Using two TNBC cell lines with different level of surface mesothelin and epithelial/mesenchymal phenotypes, we showed that, in vitro, MesobsFab promotes the recruitment and penetration of NK cells into tumor spheroids, induces potent dose-dependent cell-mediated cytotoxicity of mesothelin-positive tumor cells, cytokine secretion, and decreases cell invasiveness. MesobsFab was able to induce cytotoxicity in resting human peripheral blood mononuclear cells (PBMC), mainly through its NK cells-mediated Antibody dependent cell cytotoxicity (ADCC) activity. In vivo, the anti-tumor effect of MesobsFab depends upon a threshold of MSLN density on target cells. Collectively our data support mesothelin as a relevant therapeutic target for the subset of TNBC that overexpresses mesothelin characterized by a low overall and disease-free survival as well as the potential of MesobsFab as Antibody-based immunotherapeutics.

  • A FcγRIII-engaging Bispecific Antibody expands the range of HER2-expressing breast tumors eligible to Antibody therapy
    Oncotarget, 2014
    Co-Authors: Marc Turini, Patrick Chames, Daniel Baty, Pierre Bruhns, Brigitte Kerfelec
    Abstract:

    Trastuzumab is established as treatment of HER2high metastatic breast cancers but many limitations impair its efficacy. Here, we report the design of a Fab-like Bispecific Antibody (HER2bsFab) that displays a moderate affinity for HER2 and a unique, specific and high affinity for FcγRIII. In vitro characterization showed that ADCC was the major mechanism of action of HER2bsFab as no significant HER2-driven effect was observed. HER2bsFab mediated ADCC at picomolar concentration against HER2high, HER2low as well as trastuzumab-refractive cell lines. In vivo HER2bsFab potently inhibited HER2high tumor growth by recruitment of mouse FcγRIII and IV-positive resident effector cells and more importantly, exhibited a net superiority over trastuzumab at inhibiting HER2low tumor growth. Moreover, FcγRIIIA-engagement by HER2bsFab was independent of V/F158 polymorphism and induced a stronger NK cells activation in response to target cell recognition. Thus, taking advantage of its epitope specificity and affinity for HER2 and FcγRIIIA, HER2bsFab exhibits potent anti-tumor activity against HER2low tumors while evading most of trastuzumab Fc-linked limitations thereby potentially enlarging the number of patients eligible for breast cancer immunotherapy.

Peter Kufer - One of the best experts on this subject based on the ideXlab platform.

  • combination of rituximab with blinatumomab mt103 medi 538 a t cell engaging cd19 cd3 Bispecific Antibody for highly efficient lysis of human b lymphoma cells
    Leukemia Research, 2009
    Co-Authors: Sandrine Dargouges, Christian Brandl, Sandra Wissing, Nadja Prang, Ralf Lutterbuese, Alex Kozhich, Joann Suzich, Mathias Locher, Peter A Kiener, Peter Kufer
    Abstract:

    We have compared the cytotoxic activity of rituximab with that of blinatumomab (MT103/MEDI-538), a single-chain CD19-/CD3-Bispecific Antibody engaging human T cells. Blinatumomab consistently led to a higher degree of lysis of human lymphoma lines than rituximab, and was active at much lower concentration. The cytotoxicity mediated by blinatumomab and rituximab both caused a potent activation of pro-caspases 3 and 7 in target cells, a key event in induction of granzyme-mediated apoptotic cell death. Combination of rituximab with blinatumomab was found to greatly enhance the activity of rituximab, in particular at low effector-to-target cell ratios and at low Antibody concentration.

  • bites Bispecific Antibody constructs with unique anti tumor activity
    Drug Discovery Today, 2005
    Co-Authors: Evelyn Wolf, Peter Kufer, Robert Hofmeister, Bernd Schlereth, Patrick A Baeuerle
    Abstract:

    Bispecific T-cell engager molecules (BiTEs) constitute a class of Bispecific single-chain antibodies for the polyclonal activation and redirection of cytotoxic T cells against pathogenic target cells. BiTEs combine a unique set of properties that have not yet been reported for any other kind of Bispecific Antibody construct, namely extraordinary potency and efficacy against target cells at low T-cell numbers without the need for T-cell co-stimulation. Here we review novel insights into the mechanism of BiTE action, which help to explain the unique features of BiTEs, as well as data from various animal models demonstrating the outstanding therapeutic potential of BiTEs for the treatment of malignant diseases.

  • extremely potent rapid and costimulation independent cytotoxic t cell response against lymphoma cells catalyzed by a single chain Bispecific Antibody
    International Journal of Cancer, 2002
    Co-Authors: Torsten Dreier, Peter Kufer, Christian Brandl, Gert Riethmuller, Grit Lorenczewski, Patrick Hoffmann, Uwe Syring, Frank Hanakam, Ralf C Bargou, Patrick A Baeuerle
    Abstract:

    A recent study reported on an anti-CD19/anti-CD3 single-chain Bispecific Antibody (bscCD19xCD3) exhibiting high activity against human B lymphoma cell lines (Loffler et al., Blood 2000;95:2098-103). In the present study, we have explored in detail the in vitro efficacy, T-cell donor variability, binding characteristics, specificity, kinetics and interleukin-2 (IL-2) dependence of bscCD19xCD3. We found that a majority of human donor T cells tested (n = 86) gave half-maximal B-lymphoma cell lysis (ED(50)) within a range of 10-50 pg/ml bscCD19xCD3, corresponding to sub-picomolar concentrations of the Bispecific Antibody. Under identical experimental conditions, the anti-CD20 monoclonal Antibody rituximab had an at least 100,000-fold lower in vitro efficacy. The extreme potency of bscCD19xCD3 was in sharp contrast to the relatively low affinity of the anti-CD3 and anti-CD19 single-chain Fv portions in K(D) ranges of 10(-7) and 10(-9) M, respectively. Cell lysis by bscCD19xCD3 was predominantly mediated by the population of CD8/CD45RO-positive T cells. Both immortalized CD4- and CD8-positive human T-cell clones were highly active effector cells as well. Cell lysis by bscCD19xCD3 was rapid and specific. The respective parental monoclonal antibodies inhibited cell lysis and CD19-negative cells were not harmed by T cells in the presence of high amounts of bscCD19xCD3. The potent T-cell stimulus IL-2 could not markedly augment the activity of bscCD19xCD3-stimulated T cells. In conclusion, bscCD19xCD3 could redirect unstimulated cytotoxic T cells against CD19-positive cells in an unexpectedly potent, rapid and specific fashion.

  • a small Bispecific Antibody construct expressed as a functional single chain molecule with high tumor cell cytotoxicity
    Proceedings of the National Academy of Sciences of the United States of America, 1995
    Co-Authors: Matthias Mack, Gert Riethmuller, Peter Kufer
    Abstract:

    Construction of a Bispecific single-chain Antibody derivative is described that consists of two different single-chain Fv fragments joined through a Gly-Ser linker. One specificity of the two Fv fragments is directed against the CD3 antigen of human T cells and the other is directed against the epithelial 17-1A antigen; the latter had been found in a clinical trial to be a suitable target for Antibody therapy of minimal residual colorectal cancer. The construct could be expressed in CHO cells as a fully functional protein, while its periplasmic expression in Escherichia coli resulted in a nonfunctional protein only. The antigen-binding properties of the Bispecific single-chain Antibody are indistinguishable from those of the corresponding univalent single-chain Fv fragments. By redirecting human peripheral T lymphocytes against 17-1A-positive tumor cells, the Bispecific Antibody proved to be highly cytotoxic at nanomolar concentrations as demonstrated by 51Cr release assay on various cell lines. The described Bispecific construct has a molecular mass of 60 kDa and can be easily purified by its C-terminal histidine tail on a Ni-NTA chromatography column. As Bispecific antibodies have already been shown to be effective in vivo in experimental tumor systems as well as in phase-one clinical trials, the small CD3/17-1A-Bispecific Antibody may be more efficacious than intact antibodies against minimal residual cancer cells.

Midori Shima - One of the best experts on this subject based on the ideXlab platform.

  • emicizumab a humanized Bispecific Antibody to coagulation factors ixa and x with a factor viiia cofactor activity
    International Journal of Hematology, 2020
    Co-Authors: Takehisa Kitazawa, Midori Shima
    Abstract:

    Hemophilia A is a congenital disorder caused by deficiency or malfunction of coagulation factor (F) VIII. While exogenously provided FVIII effectively reduces bleeding complications in many hemophilia A patients, multiple efforts are underway to develop new drugs to meet the needs that conventional FVIII agents do not. We have been long engaged in creating and clinically developing a humanized anti-FIXa/FX asymmetric Bispecific IgG Antibody with a FVIIIa-cofactor activity. Since this project was born from a creative and unique idea, our group recognized from the first that it would face many difficulties in the course of research including establishment of industrial manufacturability of an asymmetric Bispecific IgG Antibody. The group actually faced various challenges, but addressed all of them during about 10 years of research, and successfully created the potent humanized Bispecific Antibody, emicizumab. Emicizumab has showed clinical benefits in the human trials among which the first one was started in 2012, and has been currently approved in US, EU, Japan, and some other countries. It is now expected to improve the quality of life of patients and their families. In this article, we review the course of the research and clinical development of emicizumab, and describe its molecular characteristics.

  • modified clot waveform analysis to measure plasma coagulation potential in the presence of the anti factor ixa factor x Bispecific Antibody emicizumab comment
    Journal of Thrombosis and Haemostasis, 2018
    Co-Authors: Keiji Nogami, Takehisa Kitazawa, Tetsuhiro Soeda, Tomoko Matsumoto, Yuka Tabuchi, Nobuo Arai, Midori Shima
    Abstract:

    Essentials The activated partial prothrombin time (aPTT) cannot predict the activity of emicizumab (Emi). Adjusted clot waveform analyses using a prothrombin time (PT)/aPTT initiator were developed. Activity of Emi in the co-presence of factor VIII or bypassing agents was quantified. This assay is useful for assessing coagulation potential in Emi-treated hemophilia A. Summary Background Emicizumab is an anti-activated factor IX/FX Bispecific Antibody that mimics activated FVIII cofactor function. Emicizumab does not require activation by thrombin, and its effect on shortening the activated partial thromboplastin time (APTT) is much greater than that of FVIII. Therefore, the APTT has limited utility in hemophilia A (HA) patients treated with emicizumab. Aim To evaluate the global coagulation potential of emicizumab. Methods Clot waveform analysis (CWA) with prothrombin time (PT)/APTT mixed reagents was used to define hemostatic monitoring protocols in HA patients. A modified parameter, adjusted-|min1| (Ad|min1|), was developed. Maximum and minimum percentage transmittance were defined as 100% and 0% in the precoagulation and postcoagulation phases, respectively. Ad|min1| was calculated as an index of the maximum velocity of the coagulation process. Results Ad|min1| obtained with mixed-trigger reagent (PT/APTT/buffer, 1 : 15 : 135) in the presence of emicizumab optimally corresponded to the conversion rate estimated in animals; 0.2-0.4 IU dL-1 equivalent FVIII per 1 μg mL-1 emicizumab). Ex vivo addition of emicizumab to HA plasma with or without inhibitors resulted in concentration-dependent increases in Ad|min1|, with some individual variations. The addition of various concentrations of FVIII to HA plasma mixed with emicizumab resulted in dose-dependent increases in Ad|min1|. Similarly, mixtures of activated prothrombin complex concentrate and emicizumab added to HA plasma resulted in dose-dependent increases in Ad|min1|. In contrast, enhanced coagulation potential appeared to be better defined by the clot time than by Ad|min1| in experiments using recombinant activated FVII. Conclusion The PT/APTT reagent-triggered adjusted CWA could provide a useful means of assessing global coagulation potential in emicizumab-treated HA patients, with enhanced activity neither masking nor being masked by FVIII or bypassing agents.

  • factor viii mimetic function of humanized Bispecific Antibody in hemophilia a
    The New England Journal of Medicine, 2016
    Co-Authors: Midori Shima, Hideji Hanabusa, Masashi Taki, Tadashi Matsushita, Tetsuji Sato, Katsuyuki Fukutake, Naoki Fukazawa, Koichiro Yoneyama, Hiroki Yoshida, Keiji Nogami
    Abstract:

    BackgroundIn patients with severe hemophilia A, standard treatment is regular prophylactic and episodic intravenous infusions of factor VIII. However, these treatments are burdensome, especially for children, and may lead to the formation of anti–factor VIII alloantibodies (factor VIII inhibitors). Emicizumab (ACE910), a humanized Bispecific Antibody mimicking the cofactor function of factor VIII, was developed to abate these problems. MethodsWe enrolled 18 Japanese patients with severe hemophilia A (with or without factor VIII inhibitors) in an open-label, nonrandomized, interindividual dose-escalation study of emicizumab. The patients received subcutaneous emicizumab weekly for 12 weeks at a dose of 0.3, 1.0, or 3.0 mg per kilogram of body weight (cohorts 1, 2, and 3, respectively). The end points were safety and pharmacokinetic and pharmacodynamic profiles. An additional, exploratory end point was the annualized bleeding rate, calculated as 365.25 times the number of bleeding episodes, divided by the n...

  • a first in human phase 1 study of ace910 a novel factor viii mimetic Bispecific Antibody in healthy subjects
    Blood, 2016
    Co-Authors: Naoki Uchida, Naoki Fukazawa, Koichiro Yoneyama, Takehiko Sambe, Takehiko Kawanishi, Shinichi Kobayashi, Midori Shima
    Abstract:

    ACE910 is a recombinant humanized Bispecific Antibody that binds to activated factor IX and factor X and mimics the cofactor function of factor VIII (FVIII). This first-in-human study examined the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ACE910 in healthy male adults. A total of 40 Japanese and 24 white subjects were randomized to receive a single subcutaneous injection of ACE910 (Japanese: 0.001, 0.01, 0.1, 0.3, or 1 mg/kg; white: 0.1, 0.3, or 1 mg/kg; n = 6 per dose group) or placebo (n = 2 per dose group). ACE910 exhibited a linear PK profile and had a half-life of ∼4 to 5 weeks. In FVIII-neutralized plasma, ACE910 shortened activated partial thromboplastin time and increased peak height of thrombin generation in a dose-dependent manner. All adverse events were nonserious and did not lead to any subject’s withdrawal. Neither clinical findings nor laboratory abnormalities indicating hypercoagulability were observed. Two of 48 subjects receiving ACE910 (1 Japanese and 1 white) were positive for anti-ACE910 antibodies (anti-drug antibodies [ADAs]). One subject tested positive for ADAs both before and after ACE910 administration, whereas the other became ADA positive after receiving ACE910. The PK and PD profiles of ACE910 were similar in healthy Japanese and white subjects and suggest that ACE910 will be an effective and convenient prophylactic treatment of hemophilia A. This trial was registered at www.clinicaltrials.jp as #JapicCTI-121934.

  • anti factor ixa x Bispecific Antibody ace910 hemostatic potency against ongoing bleeds in a hemophilia a model and the possibility of routine supplementation
    Journal of Thrombosis and Haemostasis, 2014
    Co-Authors: Atsushi Muto, Kazutaka Yoshihashi, Minako Takeda, Takehisa Kitazawa, Tetsuhiro Soeda, Tomoyuki Igawa, Kenta Haraya, Yuichiro Sakamoto, Yoshiki Kawabe, Midori Shima
    Abstract:

    SummaryBackground We previously reported that a humanized anti-factor IXa/X Bispecific Antibody, hBS23, mimics the function of FVIII even in the presence of FVIII inhibitors, and has preventive hemostatic activity against bleeding in an animal model of acquired hemophilia A. After further molecular engineering of hBS23, we recently identified an improved humanized Bispecific Antibody, ACE910, for clinical investigation. Objectives To elucidate the in vivo hemostatic potency of ACE910 by examining its effect against ongoing bleeds, and to determine its pharmacokinetic parameters for discussion of its potency for prophylactic use. Methods A non-human primate model of acquired hemophilia A was established by injecting anti-primate FVIII neutralizing Antibody. When bleeds emerged following an artificial bleed-inducing procedure, either ACE910 or recombinant porcine FVIII (rpoFVIII) was intravenously administered. rpoFVIII was additionally administered twice daily on the following 2 days. Bleeding symptoms were monitored for 3 days. A pharmacokinetic study and multiple-dosing simulations of ACE910 were also performed. Results A single bolus of 1 or 3 mg kg−1 ACE910 showed hemostatic activity comparable to that of 10 U kg−1 (twice daily) rpoFVIII against ongoing bleeds. The determined ACE910 pharmacokinetic parameters included a long half-life (3 weeks) and high subcutaneous bioavailability (nearly 100%). The simulation results based on pharmacokinetic parameters indicated that the above hemostatic level could be maintained with once-weekly subcutaneous administration of ACE910, suggesting the possibility of more effective prophylaxis. Conclusions ACE910 may offer an alternative on-demand treatment option for patients with hemophilia A, as well as user-friendly and aggressive routine supplementation.

Patrick A Baeuerle - One of the best experts on this subject based on the ideXlab platform.

  • bites Bispecific Antibody constructs with unique anti tumor activity
    Drug Discovery Today, 2005
    Co-Authors: Evelyn Wolf, Peter Kufer, Robert Hofmeister, Bernd Schlereth, Patrick A Baeuerle
    Abstract:

    Bispecific T-cell engager molecules (BiTEs) constitute a class of Bispecific single-chain antibodies for the polyclonal activation and redirection of cytotoxic T cells against pathogenic target cells. BiTEs combine a unique set of properties that have not yet been reported for any other kind of Bispecific Antibody construct, namely extraordinary potency and efficacy against target cells at low T-cell numbers without the need for T-cell co-stimulation. Here we review novel insights into the mechanism of BiTE action, which help to explain the unique features of BiTEs, as well as data from various animal models demonstrating the outstanding therapeutic potential of BiTEs for the treatment of malignant diseases.

  • extremely potent rapid and costimulation independent cytotoxic t cell response against lymphoma cells catalyzed by a single chain Bispecific Antibody
    International Journal of Cancer, 2002
    Co-Authors: Torsten Dreier, Peter Kufer, Christian Brandl, Gert Riethmuller, Grit Lorenczewski, Patrick Hoffmann, Uwe Syring, Frank Hanakam, Ralf C Bargou, Patrick A Baeuerle
    Abstract:

    A recent study reported on an anti-CD19/anti-CD3 single-chain Bispecific Antibody (bscCD19xCD3) exhibiting high activity against human B lymphoma cell lines (Loffler et al., Blood 2000;95:2098-103). In the present study, we have explored in detail the in vitro efficacy, T-cell donor variability, binding characteristics, specificity, kinetics and interleukin-2 (IL-2) dependence of bscCD19xCD3. We found that a majority of human donor T cells tested (n = 86) gave half-maximal B-lymphoma cell lysis (ED(50)) within a range of 10-50 pg/ml bscCD19xCD3, corresponding to sub-picomolar concentrations of the Bispecific Antibody. Under identical experimental conditions, the anti-CD20 monoclonal Antibody rituximab had an at least 100,000-fold lower in vitro efficacy. The extreme potency of bscCD19xCD3 was in sharp contrast to the relatively low affinity of the anti-CD3 and anti-CD19 single-chain Fv portions in K(D) ranges of 10(-7) and 10(-9) M, respectively. Cell lysis by bscCD19xCD3 was predominantly mediated by the population of CD8/CD45RO-positive T cells. Both immortalized CD4- and CD8-positive human T-cell clones were highly active effector cells as well. Cell lysis by bscCD19xCD3 was rapid and specific. The respective parental monoclonal antibodies inhibited cell lysis and CD19-negative cells were not harmed by T cells in the presence of high amounts of bscCD19xCD3. The potent T-cell stimulus IL-2 could not markedly augment the activity of bscCD19xCD3-stimulated T cells. In conclusion, bscCD19xCD3 could redirect unstimulated cytotoxic T cells against CD19-positive cells in an unexpectedly potent, rapid and specific fashion.