T Cell Costimulus-Independent and Very Efficacious Inhibition of Tumor Growth in Mice Bearing Subcutaneous or Leukemic Human B Cell Lymphoma Xenografts by a CD19-/CD3- Bispecific Single-Chain Antibody Construct

Abstract

We have recently demonstrated that a recombinant single-chain bispecific Ab construct, bscCD19xCD3, in vitro induces rapid B lymphoma-directed cytotoxicity at picomolar concentrations with unstimulated peripheral T cells. In this study, we show that treatment of nonobese diabetic SCID mice with submicrogram doses of bscCD19xCD3 could prevent growth of s.c. human B lymphoma xenografts and essentially cured animals when given at an early tumor stage. The effect was dose dependent, dependent on E:T ratio and the time between tumor inoculation and administration of bscCD19xCD3. No therapeutic effect was seen in the presence of human lymphocytes alone, a vehicle control, or with a bispecific single-chain construct of identical T cell-binding activity but different target specificity. In a leukemic nonobese diabetic SCID mouse model, treatment with bscCD19xCD3 prolonged survival of mice in a dose-dependent fashion. The human lymphocytes used as effector cells in both animal models did not express detectable T cell activation markers at the time of coinoculation with tumor cells. The bispecific Ab therefore showed an in vivo activity comparable to that observed in cell culture with respect to high potency and T cell costimulus independence. These properties make bscCD19xCD3 superior to previously investigated CD19 bispecific Ab-based therapies.

Translation and Clinical Development of Bispecific T‐cell Engaging Antibodies for Cancer Treatment

“…In preclinical species, these relatively small (blinatumomab is 55 kDa) fusion proteins have a terminal phase half‐life of only a few hours 32, 33. Full‐length monoclonal antibodies typically have a 21‐day half‐life, owing to neonatal Fc receptor (FcR n )‐mediated recycling.…”

“…Because blinatumomab is not crossreactive with murine CD3, human T cells were administered as effector cells for redirected target cell lysis, but costimulatory agents were not required 32. Several other BiTE® antibody constructs are in various stages of clinical development, including AMG 211/MEDI‐565, AMG 212, AMG 420, and AMG 330.…”

Novel antibodies as anticancer agents

“…The main antigens that have been used as targets for bispecific antibodies are overexpressed by tumor cells, including EGFR (Witlox et al, 2002;Reusch et al, 2006), HER2 (Zhu et al, 1996;Maletz et al, 2001a), CD19 (Haagen et al, 1994;Csoka et al, 1996;Chen et al, 1998a, b;Kipriyanov et al, 1998;Loffler et al, 2000b;Manzke et al, 2001a, b;Dreier et al, 2003c), CD20 (Brandl et al, 1999;Xiong et al, 2002;Yu et al, 2005), EpCAM (Maletz et al, 2001b;Wimberger et al, 2003), MUC-1 (Katayose et al, 1996) and CEA (FitzGerald et al, 1997;Holliger et al, 1999;Korn et al, 2004).…”

“…The BiTEs molecules, which contain anti-CD3 antibody, have the unique ability to achieve target cell lysis at low T-cell numbers (Hoffmann et al, 2005a) without the need for T-cell costimulation (Dreier et al, 2002a(Dreier et al, , 2003b. Monovalent binding to the CD3 complex is not sufficient to lead a full T-cell activation.…”

“…To date, a great variety of target cells have been tested for lysis mediated by BiTEs, and no fully resistant tumor cell line expressing the target antigen has been identified (Wolf et al, 2005). MT103, a CD19-specific BiTE, showed a high ex vivo response against blood samples from B-cell lymphoma patients (Loffler et al, 2003), and was efficacious in a severe combined immunodeficiency (SCID) mouse model (Dreier et al, 2003a). It has been shown in chimpanzees that MT103 causes cumulative loss of peripheral B lymphocytes (Schlereth et al, 2006).…”