T cells armed with anti-CD3 × anti-CD20 bispecific antibody enhance killing of CD20+ malignant B cells and bypass complement-mediated rituximab resistance in vitro

Gall, Jonathan M.; Davol, Pamela A.; Grabert, Ryan C.; Deaver, M.W.; Lum, Lawrence G.

doi:10.1016/j.exphem.2005.01.007

Cited by 56 publications

(59 citation statements)

References 22 publications

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“…An assay for in vitro anti-SK-BR-3 specific antibody synthesis was performed as described. 9 , 21 Specific antibodies were detected by a whole cell ELISA and antigen specific ELISA. 13,22 ( supplemental information ).…”

Section: Methodsmentioning

confidence: 99%

Immune T cells can transfer and boost anti-breast cancer immunity

et al. 2018

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This proof-of-concept study investigates the immune effects in metastatic breast cancer (MBC) patients after “vaccination” with activated T cells (ATC) armed with anti-CD3 x anti-HER2 bispecific antibody (HER2 BATs) followed by immune consolidation with immune ATC “boost” after high dose chemotherapy (HDC) and autologous stem cell transplant (SCT). Approximately 2 weeks after completion of vaccination portion of the study, immune T cells were obtained by leukopheresis, activated and expanded ex vivo and re-infused after HDC and SCT to test the hypothesis that transfer of immune unarmed ATC would accelerate reconstitution of anti-tumor activity after SCT. Eight metastatic breast cancer (MBC) patients received 8 infusions of HER2 BATs, low dose IL-2, and GM-CSF in the first part of the protocol to induce adaptive cellular and humoral responses. In the “boost” portion of the protocol, 6 of 8 patients received multiple infusions of unarmed ATC post SCT. There were no dose-limiting toxicities or delays in engraftment. Four of 6 patients tested for the immune correlative studies exhibited increases in anti-breast cancer (BrCa) cytotoxicity, antigen specific IFN-γ Elispots, anti-BrCa antibodies and increased IL-12 and Th1 serum cytokine levels after HER2 BATs infusions. Anti-BrCa tumor responses were seen as early as 2 weeks after SCT and persisted up to 2 years post-SCT. One out of 6 patients’ rapidly progressed and showed poor immune responses and high Th2 cytokine levels. There was a significant correlation (p < 0.002) between time to progression (TTP) and anti-BrCa cytotoxicity by immune T cells. This is the first study to show that adoptive transfer of immune T cells after SCT accelerates reconstitution of anti-BrCa specific immunity and correlates with delay TTP.

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Section: Methodsmentioning

confidence: 99%

Immune T cells can transfer and boost anti-breast cancer immunity

et al. 2018

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“…Furthermore, a CD3/EGFR BiTE ® caused acute toxicity in cynomolgus monkeys likely due to EGFR expression in normal tissue [10]. Not surprisingly, most CD3 bispecific proteins currently in clinical trials are targeting receptors whose expression is confined to the hematopoietic lineage (CD19, CD20, CD123) [6,11,12], or receptors with exceptionally high tumor specificity, such as carcinoembryonic antigen (CEA) [13], prostate-specific membrane antigen (PSMA) [14] or MHCI-gp100 complex [15]. Thus, the applicability of T cell redirection with currently available technologies is limited to antigens with extraordinarily high tumor specificity, which impedes the application to many solid tumor types, where no antigens with comparable high specificity are available.…”

Section: Introductionmentioning

confidence: 99%

Bispecific CD3/HER2 Targeting FynomAb Induces Redirected T Cell-Mediated Cytolysis with High Potency and Enhanced Tumor Selectivity

et al. 2015

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CD3 bispecific therapies retargeting T cells to tumors have recently demonstrated striking activity in patients. Several CD3 bispecific antibodies directed against various tumor targets are currently being investigated in the clinic across different tumors. One limitation of these therapies is the risk of target-related toxicity due to low-level expression of tumor antigen in normal tissue. In this study we have engineered a bispecific CD3/HER2 FynomAb, COVA420, which redirects T cells with high potency and selectivity to tumor cells with high HER2 expression in vitro and in vivo. COVA420 activity depends on high HER2 density as no activity was observed on cells with lower HER2 levels as found in human normal tissue. These results suggest that COVA420 may spare normal tissue expressing low levels of HER2 while still having uncompromised efficacy on tumor cells OPEN ACCESSAntibodies 2015, 4 427 with high HER2 expression. This concept may be applied to other cancer antigens that otherwise cannot be targeted by T cell redirecting approaches, and may therefore expand the applicability of CD3 bispecific FynomAbs to a larger number of solid tumors.

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“…A hexavalent antibody construct linking four FAB fragments of epratuzumab (anti-CD22) with the anti-CD20 antibody veltuzumab was shown to act more specifically against malignant B-cells compared to the parental antibodies [104]. BiTEs directed against CD3 and CD20 have been developed and investigated in vitro [105,106]. Recently, the CD20/CD3 bispecific antibody with a Fc-domain and, therefore, trifunctional capacity, Bi20 (fBTA05), has been developed and shows remarkable activity against CD20+ lymphoma cells in preclinical studies by engaging and activating T-cells and inducing Fc-mediated cellular response [107].…”

Section: Bispecific Antibodiesmentioning

confidence: 99%

Monoclonal Antibodies in Paediatric Acute Lymphoblastic Leukemia

Stackelberg

2011

New Agents for the Treatment of Acute Lymphoblastic Leukemia

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In 1975, Kohler et al. produced the first monoclonal antibodies (moAbs) by fusing a myeloma cell line with a specific antibody-producing B cell. This combined the unlimited growth potential of myeloma cells with the predetermined antibody specificity of normal immune spleen cells from an immunized mouse. The technique called somatic cell hybridization results in a hybridoma [1]. Humans receiving murine moAbs produce human anti-mouse antibodies (HAMA) leading to inactivation of the moAbs and allergic complications. The chimerization or humanization of moAbs via innovative recombinant DNA technology leads to a better tolerance to the compounds and has allowed for using the natural effector mechanisms of destroying with moAb-coated targets [2]. Whereas chimeric moAbs have antigenbinding parts (variable regions) of the mouse antibody and the effector parts (constant region, Fc) of a human antibody, in humanized compounds the mousederiving part of the moAb is reduced to the antigen-binding site (hypervariable region). The methodological approach to engineer the composition of moAbs is a broad and intensively developing field [3]. Structure of Monoclonal Antibodies (moAbs)A physiological IgG antibody consists of four polypeptide chains, two identical heavy chains and two identical light chains, which are covalently linked by interchain disulfide bonds. The chains have a variable (V) and a constant (C) region. The constant region of light chains consists of one C-domain, and the heavy chains have A. von Stackelberg (*) Pädiatrische Onkologie/Hämatologie,

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T cells armed with anti-CD3 × anti-CD20 bispecific antibody enhance killing of CD20+ malignant B cells and bypass complement-mediated rituximab resistance in vitro

Cited by 56 publications

References 22 publications

Immune T cells can transfer and boost anti-breast cancer immunity

Immune T cells can transfer and boost anti-breast cancer immunity

Bispecific CD3/HER2 Targeting FynomAb Induces Redirected T Cell-Mediated Cytolysis with High Potency and Enhanced Tumor Selectivity

Monoclonal Antibodies in Paediatric Acute Lymphoblastic Leukemia

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