The novel bispecific diabody αCD40/αCD28 strengthens leukaemic dendritic cell‐induced T‐cell reactivity

Dendritic cell (DC)‐based immunotherapy faces new challenges because the efficacy of DC vaccines in clinical trials has been inconsistent. Strategies to improve immune responses induced by DC are currently being explored. We have recently shown the feasibility of generating fully functional DC from acute myeloid leukaemic (AML) blasts, but with varying expression levels of the important costimulatory molecule CD86. To overcome this variability, we developed a novel bispecific diabody that simultaneously and agonistically targeted CD40 on AML‐DC and CD28 on naïve T cells. Beside optimization of CD28‐mediated signalling, the resulting cellular cross‐linking was also hypothesized to increase the strength and duration of T cell/AML‐DC interactions, thus increasing T‐cell responsiveness to AML antigens. The αCD40/αCD28‐bispecific diabody was found to bind to its target antigens and provoked increased T‐cell–DC cluster formation. The αCD40/αCD28 diabody is capable of increasing T‐cell proliferation induced by AML‐DC as well as the induction of DC maturation. Importantly, priming efficacy of tumour‐specific cytotoxic T cells can also be improved by cross‐linking AML‐DC and T cells with the αCD40/αCD28 diabody. We propose that the αCD40/αCD28‐bispecific diabody can serve as a potent therapeutic tool to effectively augment anti‐tumour T‐cell responses elicited by AML‐DC.

[1]  Nicki Panoskaltsis,et al.  Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. , 2006, The New England journal of medicine.

[2]  E. Hooijberg,et al.  Human telomerase reverse transcriptase Æ MoDC : Monocyte-derived dendritic cell Æ D NGFR : Truncated form of nerve growth factor receptor Æ PBMC : Peripheral blood mononuclear cell , 2006 .

[3]  J. Becker,et al.  CD28‐mediated costimulation impacts on the differentiation of DC vaccination‐induced T cell responses , 2006, Clinical and experimental immunology.

[4]  G. Ossenkoppele,et al.  Leukemia-derived dendritic cells: towards clinical vaccination protocols in acute myeloid leukemia. , 2006, Haematologica.

[5]  G. Ossenkoppele,et al.  Divergent Autologous T Cell Responses to Leukaemic Dendritic Cells during Remission in Acute Promyelocytic Leukaemia , 2005, Cellular oncology : the official journal of the International Society for Cellular Oncology.

[6]  P. Leclerc,et al.  Differential effect of agonistic anti-CD40 on human mature and immature dendritic cells: the Janus face of anti-CD40. , 2005, Blood.

[7]  G. Schuurhuis,et al.  Quantification of T‐cell–mediated apoptosis in heterogeneous leukemia populations using four‐color multiparameter flow cytometry , 2005, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[8]  G. Ossenkoppele,et al.  Leukemia-derived dendritic cells in acute myeloid leukemia exhibit potent migratory capacity , 2005, Leukemia.

[9]  T. Geijtenbeek,et al.  Neutrophils mediate immune modulation of dendritic cells through glycosylation-dependent interactions between Mac-1 and DC-SIGN , 2005, The Journal of experimental medicine.

[10]  Sam C. Noureddini,et al.  A single-component CD40-targeted adenovirus vector displays highly efficient transduction and activation of dendritic cells in a human skin substrate system. , 2005, Molecular pharmaceutics.

[11]  F. Nestle,et al.  Dendritic-cell-based therapeutic vaccination against cancer. , 2005, Current opinion in immunology.

[12]  M. Little,et al.  Effect of tetravalent bispecific CD19×CD3 recombinant antibody construct and CD28 costimulation on lysis of malignant B cells from patients with chronic lymphocytic leukemia by autologous T cells , 2004, International journal of cancer.

[13]  P. Circosta,et al.  Leukemia-Derived Immature Dendritic Cells Differentiate into Functionally Competent Mature Dendritic Cells That Efficiently Stimulate T Cell Responses1 , 2004, The Journal of Immunology.

[14]  J. Trapani,et al.  A functional role for CD28 costimulation in tumor recognition by single-chain receptor-modified T cells , 2004, Cancer Gene Therapy.

[15]  F. Legall,et al.  Recent advances in the generation of bispecific antibodies for tumor immunotherapy. , 2004 .

[16]  S. Kipriyanov,et al.  Recent advances in the generation of bispecific antibodies for tumor immunotherapy. , 2004, Current opinion in drug discovery & development.

[17]  Oreste Acuto,et al.  CD28-mediated co-stimulation: a quantitative support for TCR signalling , 2003, Nature Reviews Immunology.

[18]  Erik Hooijberg,et al.  In Vitro Generation and Life Span Extension of Human Papillomavirus Type 16-Specific, Healthy Donor-Derived CTL Clones 1 , 2003, The Journal of Immunology.

[19]  M. Little,et al.  Effect of domain order on the activity of bacterially produced bispecific single-chain Fv antibodies. , 2003, Journal of molecular biology.

[20]  D. Curiel,et al.  CD40-targeted adenoviral gene transfer to dendritic cells through the use of a novel bispecific single-chain Fv antibody enhances cytotoxic T cell activation. , 2003, Vaccine.

[21]  G. Ossenkoppele,et al.  Serum-free generation of antigen presenting cells from acute myeloid leukaemic blasts for active specific immunisation , 2003, Cancer Immunology, Immunotherapy.

[22]  J. Trapani,et al.  Rejection of Syngeneic Colon Carcinoma by CTLs Expressing Single-Chain Antibody Receptors Codelivering CD28 Costimulation , 2003, The Journal of Immunology.

[23]  D. Ridgway.  The First 1000 Dendritic Cell Vaccinees , 2003, Cancer investigation.

[24]  G. Schuurhuis,et al.  Rapid generation of antigen-presenting cells from leukaemic blasts in acute myeloid leukaemia , 2003, Cancer Immunology, Immunotherapy.

[25]  S. Chattopadhyay,et al.  CD28 signaling in neutrophil induces T-cell chemotactic factor(s) modulating T-cell response. , 2003, Human immunology.

[26]  J. Trapani,et al.  Rejection of Syngeneic Colon Carcinoma by CTLs Expressing Single-Chain Antibody Receptors Codelivering CD28 Costimulation1 , 2002, The Journal of Immunology.

[27]  Michael S. Kuhns,et al.  CTLA-4: new insights into its biological function and use in tumor immunotherapy , 2002, Nature Immunology.

[28]  T. D. de Gruijl,et al.  MUTZ-3, a human cell line model for the cytokine-induced differentiation of dendritic cells from CD34+ precursors. , 2002, Blood.

[29]  S. Kipriyanov.  Generation of bispecific and tandem diabodies. , 2002, Methods in molecular biology.

[30]  M L Brereton,et al.  Stimulation of autologous proliferative and cytotoxic T-cell responses by "leukemic dendritic cells" derived from blast cells in acute myeloid leukemia. , 2001, Blood.

[31]  T. Valerius,et al.  Preclinical and clinical data with bispecific antibodies recruiting myeloid effector cells for tumor therapy. , 2001, Critical reviews in oncology/hematology.

[32]  G. Schuurhuis,et al.  Large populations of non-clonogenic early apoptotic CD34-positive cells are present in frozen-thawed peripheral blood stem cell transplants , 2001, Bone Marrow Transplantation.

[33]  V. Diehl,et al.  Locoregional treatment of low‐grade B‐cell lymphoma with CD3×CD19 bispecific antibodies and CD28 costimulation: II. Assessment of cellular immune responses , 2001, International journal of cancer.

[34]  V. Diehl,et al.  Locoregional treatment of low‐grade B‐cell lymphoma with CD3×CD19 bispecific antibodies and CD28 costimulation: I. Clinical phase I evaluation , 2001, International journal of cancer.

[35]  H. Kolb,et al.  Leukemic dendritic cells generated in the presence of FLT3 ligand have the capacity to stimulate an autologous leukemia-specific cytotoxic T cell response from patients with acute myeloid leukemia , 2001, Leukemia.

[36]  M. Little,et al.  Treatment of Human B Cell Lymphoma Xenografts with a CD3 × CD19 Diabody and T Cells1 , 2000, The Journal of Immunology.

[37]  M. Pfreundschuh,et al.  Initiation of humoral and cellular immune responses in patients with refractory Hodgkin's disease by treatment with an anti-CD16/CD30 bispecific antibody , 2000, Cancer Immunology, Immunotherapy.

[38]  J. V. D. van de Winkel,et al.  Immunotherapeutic perspective for bispecific antibodies. , 2000, Immunology today.

[39]  T. Schumacher,et al.  Enrichment of an antigen-specific T cell response by retrovirally transduced human dendritic cells. , 1999, Cellular immunology.

[40]  W. Hahn,et al.  The telomerase catalytic subunit is a widely expressed tumor-associated antigen recognized by cytotoxic T lymphocytes. , 1999, Immunity.

[41]  P. Kalinski,et al.  Final maturation of dendritic cells is associated with impaired responsiveness to IFN-gamma and to bacterial IL-12 inducers: decreased ability of mature dendritic cells to produce IL-12 during the interaction with Th cells. , 1999, Journal of immunology.

[42]  R. Champlin,et al.  Dendritic cells derived in vitro from acute myelogenous leukemia cells stimulate autologous, antileukemic T-cell responses. , 1999, Blood.

[43]  C. June,et al.  Costimulatory approaches to adoptive immunotherapy. , 1998, Current opinion in oncology.

[44]  S. Gawlak,et al.  Construction, Expression, and Characterization of BD1-G28-5 sFv, a Single-chain Anti-CD40 Immunotoxin Containing the Ribosome-inactivating Protein Bryodin 1* , 1997, The Journal of Biological Chemistry.

[45]  B. Snedecor,et al.  High Level Secretion of a Humanized Bispecific Diabody from Escherichia coli , 1996, Bio/Technology.

[46]  J. Ledbetter,et al.  Activity of a single-chain immunotoxin that selectively kills lymphoma and other B-lineage cells expressing the CD40 antigen. , 1995, Cancer research.

[47]  W. V. van Blitterswijk,et al.  Serum-free medium for generation and propagation of functional human cytotoxic and helper T cell clones. , 1984, Journal of immunological methods.

[48]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.