The efficacy of CD3 x CD19 bispecific monoclonal antibody (BsAb) in a clonogenic assay: the effect of repeated addition of BsAb and interleukin-2.

  title={The efficacy of CD3 x CD19 bispecific monoclonal antibody (BsAb) in a clonogenic assay: the effect of repeated addition of BsAb and interleukin-2.},
  author={I. A. Haagen and Anette J. G. Geerars and Wim de Lau and Bert J.E.G. Bast and B C de Gast},
  volume={85 11},
To evaluate the potency by which human T cells are targeted and activated by bispecific monoclonal antibodies (BsAbs) to lyse tumor cells, a clonogenic assay was developed. The efficacy of a CD3 x CD19 BsAb binding to both the CD3 T-cell antigen and the CD19 B-cell antigen was already proven in 51Cr-release assays and in 3-day activation cultures. To achieve more quantitative results, a 14-day clonogenic assay, based on limiting-dilution, was performed for the determination of the initial and… 
CD8 T cell activation after intravenous administration of CD3×CD19 bispecific antibody in patients with non-Hodgkin lymphoma
A bispecific antibody directed to T and B cells (CD3×CD19 bsAb) was daily infused intravenously in escalating doses in three patients with chemotherapy-resistant non-Hodgkin lymphoma, aimed to activate T cells to kill the malignant B cells.
Clinical experience with CD3 x CD19 bispecific antibodies in patients with B cell malignancies.
Intravenously administered BsAb in an intrapatient dose escalation study of 3 patients with B cell non-Hodgkin's lymphoma showed limited toxicity (WHO grade II fever and chills) due to tumor necrosis factor-alpha (TNF-alpha) release by T cells, and treatment of patients with a lower tumor load seems to be warranted to evaluate the efficacy of CD3 x CD19 Bs Ab therapy.
A recombinant bispecific single-chain antibody, CD19 x CD3, induces rapid and high lymphoma-directed cytotoxicity by unstimulated T lymphocytes.
The described bscCD19 x CD3 molecule should be a suitable candidate to prove the therapeutic benefit of bispecific antibodies in the treatment of non-Hodgkin lymphoma.
A fully human CD19/CD3 bi-specific antibody triggers potent and specific cytotoxicity by unstimulated T lymphocytes against non-Hodgkin’s lymphoma
A fully human recombinant single chain Fv BsAb against CD19 and CD3 that was an effective treatment in an animal model of non-Hodgkin’s lymphoma (NHL) and efficiently inhibited tumour growth in SCID mice of NHL.
The effect of dexamethasone on polyclonal T cell activation and redirected target cell lysis as induced by a CD19/CD3-bispecific single-chain antibody construct
Dexamethasone did not detectably inhibit the cytotoxic activity of MT103-activated T cells against a human B lymphoma line as investigated with lymphocytes from 12 human donors, and qualify as a potential co-medication for therapeutic BiTE molecules and other cytot toxic T cell therapies for treatment of cancer.
Performance of CD3xCD19 bispecific monoclonal antibodies in B cell malignancy.
The experiments performed to test a new immunotherapeutic approach for the treatment of B cell malignancy show that the CD3xCD19 BsAb has a potential as a therapeutic agent in B cellmalignancy.
Characterization of an anti-human ovarian carcinomaxanti-human CD3 bispecific single-chain antibody with an albumin-original interlinker.
The scBsAb showed nearly identical ligand binding properties at each site relative to the individual monovalent single-chain antibody prototype molecules and could bridge SKOV3 and human T cell line Jurkat, which expresses CD3 antigens on the surface of cells together.
Efficient elimination of chronic lymphocytic leukaemia B cells by autologous T cells with a bispecific anti-CD19/anti-CD3 single-chain antibody construct
It is shown that bscCD193CD3 induces T-cell-mediated depletion of nonmalignant B cells in all four cases and depletion of primary lymphoma cells in 22 out of 25 cases, and evidence is provided that B-CLL cell depletion by bSCCD3CD3 is mediated at least in part by apoptosis via the caspase pathway.
A novel recombinant bispecific single-chain antibody, bscWue-1 × CD3, induces T-cell-mediated cytotoxicity towards human multiple myeloma cells
It is shown that bscWue-1 × CD3 induces efficient and selective T-cell-mediated cell death of NCI-H929 cells and primary myeloma cells in nine out of 11 cases and is efficacious even at low E:T ratios, and with or without additional T- cell pre- or costimulation.
Extremely potent, rapid and costimulation‐independent cytotoxic T‐cell response against lymphoma cells catalyzed by a single‐chain bispecific antibody
A recent study reported on an anti‐CD19/anti‐CD3 single‐chain bispecific antibody (bscCD19xCD3) exhibiting high activity against human B lymphoma cell lines (Löffler et al., Blood 2000;95:2098–103).


Killing of Autologous B-Lineage Malignancy Using CD3 x CD19 Bispecific Monoclonal Antibody in End Stage Leukemia and Lymphoma
Various types of experiments showed that efficient CD3 x CD19 BsAb-mediated cytolytic capacity was not dependent on expression of either of these surface proteins, which contrasts with normal major histocompatibility complex-restricted antigen-specific cytotoxicity and may be essential for effective in vivo application of this Bs Ab.
Bispecific antibody therapy of two murine B-cell lymphomas.
Immunotherapy of tumor bearing animals demonstrated that bsAbs could efficiently target T cells towards the tumor cells, that tumor cell--T cell bridging is established in vivo, and that both T cell subsets contribute to tumor regression resulting in long-term survival and cure of the lymphomas.
Functional studies with anti-CD3 heavy chain isotype switch-variant monoclonal antibodies. Accessory cell-independent induction of interleukin 2 responsiveness in T cells by epsilon-anti-CD3.
It was demonstrated that the epsilon-anti-CD3 antibody, in comparison with the other variant mAb, has a relatively low avidity for the CD3 antigen, possibly as a result of monovalent binding.
T-cell killing of target cells induced by hybrid antibodies: comparison of two bispecific monoclonal antibodies.
Mixed isotype hybrid antibodies may have some advantages for eliciting T-cell-mediated killing of tumor cell targets by exhibiting a better therapeutic ratio of target cell to effector cell cytotoxicity.
Effective purging of bone marrow by a combination of immunorosette depletion and complement lysis.
The combination of the two methods results in a highly efficient purging procedure for the removal of cALL+ cells from autologous bone marrow cells.
The improved lytic function and in vivo efficacy of monovalent monoclonal CD3 antibodies
In a preliminary clinical study in one patient with a T lymphoma in leukemic phase this monovalent CD3 antibody was found to be very effective in depleting CD3 tumor cells in the peripheral blood and bone marrow.
Targeting of anti-tumor responses with bispecific antibodies.
When given to nude mice bearing intraperitoneal human ovarian carcinoma, targeted human T cells cause the rapid removal of most tumor cells from the peritoneum, and markedly prolong the times of survival of treated mice.
Role of the CD28 receptor in T-cell activation.
CD28 serves as the surface component of a novel signal transduction pathway that modulates T-cell lymphokine production and increases the resistance of T- cell responses to various immunosuppressive agents.
Single step separation of human T and B cells using AET treated srbc rosettes.
A technique for the single step separation of human thymus derived and Bursa equivalent lymphocytes was developed, allowing for the recovery of B lymphocytes as well as T lymphocytes in sufficient numbers to use in functional assays.