T and NK cells of B cell NHL patients exert cytotoxicity against lymphoma cells following binding of bispecific tetravalent antibody CD19 × CD3 or CD19 × CD16

Abstract

Bispecific tetravalent antibodies (TandAb) directed against the B cell surface marker CD19 and activating receptors on T or NK cells (CD19 × CD3 or CD19 × CD16) have shown promising effects in vitro and in preclinical studies. Here, we examine the cytotoxic efficacy of T and NK cells from patients with B cell Non-Hodgkin's Lymphoma (NHL) against B-lymphoma cells following the binding of the matching TandAb. The addition of CD19 × CD16 TandAb led to a threefold increase in NK cell activation in the presence of B-lymphoma cells. Similarly, T cells displayed a sevenfold increase in cytotoxic activity after the addition of CD19 × CD3 TandAb. Comparison of T and NK cell effector function of patients and healthy controls showed comparable levels of cytotoxic activity in response to lymphoma cells and no reduction in functional activity due to age, disease stage or the type and amount of previous therapy. Thus, T and NK cells of patients with B cell NHL are fully capable of being activated by therapeutic crosslinking antibodies. These results provide a rationale for the use of TandAbs for patients with B cell NHL, particularly in cases where remission with minimal residual disease could be achieved by cytotoxic chemotherapy.

Heterodimeric Bispecific Single Chain Variable Fragments (scFv) Killer Engagers (BiKEs) Enhance NK-cell Activity Against CD133+ Colorectal Cancer Cells

“…Tetravalent diabodies as well as duovalent triplebodies show high anti-cancer reactivity [21-23]. Evidence grows revealing beneficial properties in treatment with scFv including lower immunogenicy, rapid blood clearance and improved tumor penetration compared to larger molecules with high efficacy in cancer therapy when targeting immune effectors like T-cells or NK-cells [21, 22]. …”

Biomarkers of HIV-associated Cancer

“…NHL refers to a heterogeneous group of hematopoietic malignancies originating in the lymphocytes 55–57. The majority of NHL cases (85–90%) arises from B-cell progenitors and develops into the various entities largely grouped into low, intermediate, and high-grade NHL based on the treated natural history and survival patterns 58.…”

Advances in Bispecific Antibodies Engineering: Novel Concepts for Immunotherapies

“…The important role of NK cells in tumor microenvironment has been underscored as they significantly contribute to antibody cancer treatment through the ADCC mechanism. Furthermore a combination of T-cell engaging and NK engaging bispecific antibodies resulted in a synergistic effect and an amplified anti-tumor response [36]. The encouraging results obtained by bsAbs engaging T-cells and NK cells are likely to open the path for new designs targeting other immune cells (for example, eosinophils) or tumor microenvironment cells with intrinsic anti-tumor efficacy.…”

“…Besides NK cells, CD19 × CD16 bispecific diabodies can recruit other subpopulations of CD16+ effector cells, such as monocytes and macrophages. The CD19 x CD16 diabodies in combination with CD19 x CD3 bispecific diabodies have demonstrated a synergistic antitumor effect in a preclinical model of non-Hodgkin's lymphoma [36]. Furthermore, CD19 x CD16 diabodies were tested in combination with the angiogenesis inhibitor thalidomide, resulting in significant reduction of tumor size in established human B non-Hodgkin's lymphoma in severe immune deficient mice [37].…”