Abstract
Clinical results from the latest strategies for T-cell activation in cancer have fired interest in combination immunotherapies that can fully engage T-cell immunity. In this study, we describe a trastuzumab-based bispecific antibody, HER2-TDB, which targets HER2 and conditionally activates T cells. HER2-TDB specifically killed HER2-expressing cancer cells at low picomolar concentrations. Because of its unique mechanism of action, which is independent of HER2 signaling or chemotherapeutic sensitivity, HER2-TDB eliminated cells refractory to currently approved HER2 therapies. HER2-TDB exhibited potent antitumor activity in four preclinical model systems, including MMTV-huHER2 and huCD3 transgenic mice. PD-L1 expression in tumors limited HER2-TDB activity, but this resistance could be reversed by anti-PD-L1 treatment. Thus, combining HER2-TDB with anti-PD-L1 yielded a combination immunotherapy that enhanced tumor growth inhibition, increasing the rates and durability of therapeutic response.
Highlights
The recent approval of ipilimumab [1] and exciting responses observed during clinical trials of PD-1 and PD-L1 antibodies [2] clearly illustrate the potential of T cell–targeting cancer immunotherapies
An important outstanding question with T cell–engaging bispecific antibodies is whether, they too may be susceptible to T cell–suppressive resistance mechanisms following the initial T-cell response? Our results demonstrate that PD-1/PD-L1 can inhibit T-cell killing activity induced by bispecific antibodies
Antibodies produced in E. coli are not glycosylated, which results in impaired FcgR binding, which is required to mediate antibody-dependent cell-mediated cytotoxicity (ADCC; refs. 24, 25)
Summary
The recent approval of ipilimumab [1] and exciting responses observed during clinical trials of PD-1 and PD-L1 antibodies [2] clearly illustrate the potential of T cell–targeting cancer immunotherapies. The success of strategies that reinvigorate T-cell activity depends on modulation of multiple stimulatory and inhibitory events that enable an antitumor immune response [2]. Bispecific antibodies can be used to broadly harness the antitumor capacity of T-cell immunity [3]. Successful clinical use of modified and reengineered antibodies and antibody fragments is far from trivial [4]. Immunogenicity and short serum half-life are additional problems for bispecific molecules with modified antibody sequences and antibody fragment–based platforms
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