Natural Killer (NK)- and T-Cell Engaging Antibody-Derived Therapeutics

Abstract

Unmodified antibodies (abs) have been successful in the treatment of hematologic malignancies, but less so for the treatment of solid tumors. They trigger anti-tumor effects through their Fc-domains, and one way to improve their efficacy is to optimize their interaction with the effectors through Fc-engineering. Another way to empower abs is the design of bispecific abs and related fusion proteins allowing a narrower choice of effector cells. Here we review frequently chosen classes of effector cells, as well as common trigger molecules. Natural Killer (NK)-and T-cells are the most investigated populations in therapeutical approaches with bispecific agents until now. Catumaxomab, the first bispecific ab to receive drug approval, targets the tumor antigen Epithelial Cell Adhesion Molecule (EpCAM) and recruits T-cells via a binding site for the cell surface protein CD3. The next generation of recombinant ab-derivatives replaces the broadly reactive Fc-domain by a binding domain for a single selected trigger. Blinatumomab is the first clinically successful member of this class, targeting cancer cells via CD19 and engaging T-cells by CD3. Other investigators have developed related recombinant fusion proteins to recruit effectors, such as NK-cells and macrophages. The first such agents currently in preclinical and clinical development will be discussed.

T cell-recruiting triplebody 19-3-19 mediates serial lysis of malignant B-lymphoid cells by a single T cell

“…Thus NK cells may be a suitable choice of effector cells to combat minimal residual disease after an induction chemotherapy. [3] CD8 + T cells, however, are frequently present in cancer tissues in abundance, have a greater intrinsic cytotoxic potential than NK cells, and are capable of more prolonged serial lysis. [43, 44] CTLs are therefore a particularly desirable class of cytolytic effectors for cancer therapy.…”

“…[1] Recombinant proteins derived from conventional antibodies have been designed to increase tumor cell selectivity and deeper penetration into tumor tissues, and to exploit the patients' innate defense mechanisms against their disease. [2, 3] Several of the new antibody-derived agents - including immunoligands[4-6], diabodies, bispecific (bs) scFvs[7, 8], single chain triplebodies[9-12] and, most recently, a modular targeting system[13] - are based on single chain variable fragment (scFv) building blocks and lack an Fc region. While maintaining target specificity, the scFv-based agents are expected to reach deeper tissue penetration due to their reduced molecular mass.…”

“…[14, 15] The lack of an Fc region is also thought to reduce undesired side effects, which are caused by binding to Fc receptors that are exposed on cells other than the desired cytolytic effectors. [2, 3]…”

“…Another option is the engagement of autologous effector cells, such as natural killer (NK)-cells and cytotoxic T lymphocytes (CTLs), for cytolysis. [2, 3]…”

“…[9] Triplebodies can be designed to recruit different classes of effector cells via their central scFv, which is specific for an activating surface molecule such as CD16 on NK cells and macrophages[9, 10, 36], CD89 on polymorphonuclear granulocytes (PMNs)[37], or CD64 on macrophages and cytokine-stimulated PMNs. [3] The two distal binding moieties of the triplebody are capable of either monospecific bivalent targeting (example: 19-16-19)[9] or bispecific bivalent targeting (“dual-targeting”) of two different target antigens on the same cancer cell (examples: 123-16-33[36], 33-16-19[10] and HLA-DR-16-19[11]). Dual-targeting triplebodies have been shown to achieve preferential binding[4] and to mediate preferential lysis[38] of double-positive over single-positive target cells by cytolytic effectors in a mixed environment.…”