Cancer Immunotherapy by Retargeting of Immune Effector Cells via Recombinant Bispecific Antibody Constructs

Abstract

Immunotherapy has emerged as an alternative strategy to treat malignancies in addition to conventional radio- and chemotherapy. There has been a plethora of evidence that the immune system is able to control tumor outgrowth and a number of strategies have been put forward to utilize this ability for immunotherapy. However, some of these strategies have not been very efficient and their success has been limited by tumor evasion mechanisms. A promising approach to engage effector cells of the immune system overcoming some of the escape mechanisms has been introduced more than two decades ago. This approach is based on bispecific antibodies. Here we summarize the evolution of bispecific antibodies, their improvement, remaining obstacles and some controversial reports.

Simultaneous targeting of prostate stem cell antigen and prostate‐specific membrane antigen improves the killing of prostate cancer cells using a novel modular T cell‐retargeting system

“…The multifaceted nature and high plasticity of complex and heterogeneous tumors underline the requirement of novel advanced therapeutic strategies. Among targeted immunotherapies especially T cell‐engaging bsAbs represent promising candidates . By reactivating and recruiting the cytotoxic effector functions of polyclonal T cells specifically against one certain TAA on cancer cells, they are not only able to increase specificity but also to enhance potency of conventional tumor therapy.…”

“…Among novel immunotherapeutic treatment strategies especially single‐chain bispecific antibodies (bsAbs) represent attractive candidates for a targeted tumor therapy. Due to their dual‐specificity for the activating CD3‐complex on T cells and a tumor‐associated antigen (TAA), they are able to retarget T cells for an effective tumor cell killing in a TCR‐ and MHC‐independent manner . First impressive clinical results were reported for the CD19‐specific T cell‐engaging bsAb blinatumomab that was successfully used as a monotherapeutic agent for treatment of acute lymphoblastic leukemia (ALL) and non‐Hodgkin's lymphoma (NHL) patients .…”

Redirection of CD4+ and CD8+ T lymphocytes via a novel antibody‐based modular targeting system triggers efficient killing of PSCA+ prostate tumor cells

“…Within the scope of an antigen‐specific immunotherapy especially single‐chain bispecific antibodies (bsAbs) represent promising therapeutic molecules . In principle, bsAbs are generated by fusion of the minimal binding domains (fragment variable) of two monoclonal antibodies (mAbs) via flexible peptide linkers.…”

Characterization of a Novel Single-Chain Bispecific Antibody for Retargeting of T Cells to Tumor Cells via the TCR Co-Receptor CD8

“…By simultaneous binding to the activating CD3 complex and a tumor-associated surface antigen (TAA), such bsAbs (also known as BiTEs for bispecific T cell engagers) are able to trigger a T cell-mediated tumor cell lysis in a T cell receptor (TCR)- and MHC-independent manner [6]–[11]. Their highly efficient antitumor activity has already been shown both in vitro and in animal studies [4], [5]. First clinical trials with blinatumomab, the first BiTE successfully applied for treatment of B cell leukemia and lymphoma patients, support their functionality even in men [11].…”