Bispecific Antibody-Based Immune-Cell Engagers and Their Emerging Therapeutic Targets in Cancer Immunotherapy

Abstract

Cancer is the second leading cause of death worldwide after cardiovascular diseases. Harnessing the power of immune cells is a promising strategy to improve the antitumor effect of cancer immunotherapy. Recent progress in recombinant DNA technology and antibody engineering has ushered in a new era of bispecific antibody (bsAb)-based immune-cell engagers (ICEs), including T- and natural-killer-cell engagers. Since the first approval of blinatumomab by the United States Food and Drug Administration (US FDA), various bsAb-based ICEs have been developed for the effective treatment of patients with cancer. Simultaneously, several potential therapeutic targets of bsAb-based ICEs have been identified in various cancers. Therefore, this review focused on not only highlighting the action mechanism, design and structure, and status of bsAb-based ICEs in clinical development and their approval by the US FDA for human malignancy treatment, but also on summarizing the currently known and emerging therapeutic targets in cancer. This review provides insights into practical considerations for developing next-generation ICEs.

Resistance to TKIs in EGFR-Mutated Non-Small Cell Lung Cancer: From Mechanisms to New Therapeutic Strategies

“…REGN7075 is a T-cell bi-specific antibody that binds to EGFR and engages T-cells via CD28 resulting in target cell killing by T-cell activation. Its combination with an anti-PD-1 ICI, namely cemiplimab, is currently being assessed by a phase I/II clinical trial l (NCT04626635) [ 177 ]. Further clinical trials are required to establish its potential immunostimulating and antineoplastic efficacy.…”

Determination of starting dose of the T cell-redirecting bispecific antibody ERY974 targeting glypican-3 in first-in-human clinical trial

“… Group Animals (n) Autopsy (day) Dose (μg/kg/dose) Average maximum IL-6 level (pg/mL) a Clinical signs/histopathological findings 1 (Control) 3 (M) + 3 (F) 8 0 48 No finding 2 (Low) 3 (M) + 3 (F) 22 0.1 32 No finding (NOAEL) 3 (Middle) 3 (M) + 3 (F) 22 1 231 Red skin, increased body temperature, increased fibrinogen and triglyceride, decreased albumin in blood, 4 (High) 3 (M) + 3 (F) 22 10 2505 Red skin on head and/or complete body, hyperthermia, decreased body weight, low-to-no food consumption, hunched posture, decreased reactivity, decreased lymphocytes in the thymus b , increased infiltration of mononuclear cells and/or granulocytes in multiple tissues, No evidence of damages in tissues (liver, kidney, or gastrointestinal) 5 (High) 3 (M) + 3 (F) 8 10 The symptoms, level of cytokines in the blood, clinical pathological and histopathological findings in animals after administration of ERY974 are summarized. The level of IL-6 has been previously described 8 . a 8 h after administration.…”

“… The symptoms, level of cytokines in the blood, clinical pathological and histopathological findings in animals after administration of ERY974 are summarized. The level of IL-6 has been previously described 8 . a 8 h after administration.…”

“…The K D values of ERY974 to GPC3 and CD3ε measured by Surface i Resonance in which various concentrations of ERY974 was applied on the immobilized GPC3 and/or CD3 ε peptide was were 1.46 × 10 –9 and 2.07 × 10 –7 mol/L, respectively 8 .…”

“…Catumaxomab, targeting epitherial cell sdhesion molecule (EpCAM) and CD3, was the first TRAB approved for a solid tumor (i.e., EpCAM + malignant ascites) by the European Medicines Agency (EMA) in 2009, but was withdrawn due to severe toxicities 6 , 7 . However, various TRABs have been used in clinical trials 5 , 8 , 9 .…”