An Fc-Optimized CD133 Antibody for Induction of Natural Killer Cell Reactivity Against Colorectal Cancer

Abstract

The introduction of monoclonal antibodies (mAbs) has largely improved treatment options for cancer patients. The ability of antitumor mAbs to elicit antibody-dependent cellular cytotoxicity (ADCC) contributes to a large extent to their therapeutic efficacy. Many efforts accordingly aim to improve this important function by engineering mAbs with Fc parts that display enhanced affinity to the Fc receptor CD16 expressed, e.g., on natural killer (NK) cells. Here we characterized the CD133 mAb 293C3-SDIE that contains an engineered Fc part modified by the amino acid exchanges S239D/I332E—that reportedly increase the affinity to CD16—with regard to its ability to induce NK reactivity against colorectal cancer (CRC). 293C3-SDIE was found to be a stable protein with favorable binding characteristics achieving saturating binding to CRC cells at concentrations of approximately 1 µg/mL. While not directly affecting CRC cell growth and viability, 293C3-SDIE potently induced NK cell activation, degranulation, secretion of Interferon-γ, as well as ADCC resulting in potent lysis of CRC cell lines. Based on the preclinical characterization presented in this study and the available data indicating that CD133 is broadly expressed in CRC and represents a negative prognostic marker, we conclude that 293C3-SDIE constitutes a promising therapeutic agent for the treatment of CRC and thus warrants clinical evaluation.

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

“…Therefore, antibody engineering and targeting of different antigens may enhance NK cell activity and efficacy of treatment. Koerner et al previously reported an optimized anti-CD133 antibody, 293C3-SDIE for AML, which was also recently tested by Schmied et al for colorectal cancer (176,243). 293C3-SDIE was engineered with Fc portion containing the S239D and I332E substitutions to enhance binding affinity for ADCC.…”

“…Additional examination of NK cell receptor repertoire from healthy individuals and patients may be informative, to possibly screen for specific checkpoints that could synergize with 293C3-SDIE. Though the colorectal study utilizing 293C3-SDIE was conducted in-vitro, the preclinical data demonstrate it has a potent effect on NK cell activity against colorectal cell lines (243). Though additional study is required to test the effect of 293C3-SDIE against physiological solid tumors, this treatment may have important significance for NK cells against the CD133 tumor antigen, which is implicated in multiple cancer types (246).…”

Comprehensive analysis of expression profiles of long non‑coding RNAs with associated ceRNA�network involved in gastric cancer progression

“…Two upregulated lncRNAs (HOTAIR and UCA1) and two downregulated lncRNAs (LOH12CR2 and PART1) were common between the microarray, CRN and circlncRNAnet results. Several studies have previously reported that HOTAIR is an oncogene that plays a crucial role in the progression of various types of cancer (20), including gastric cancer (21,22), lung cancer (23), colorectal cancer (24), liver cancer (25), gallbladder cancer (26), breast cancer (27), cervical cancer (28), ovarian cancer (29), and prostate cancer (30). The oncogene UCA1 is known to be involved in various types of cancer, such as gastric cancer (31), breast cancer (32), bladder cancer (33) and colorectal cancer (34).…”

Induction of NK Cell Reactivity against B-Cell Acute Lymphoblastic Leukemia by an Fc-Optimized FLT3 Antibody

“…4G8-SDIE and iso-SDIE were generated by chimerization (human immunoglobulin G1/K constant region) and Fc-optimization (S239D/I332E modification) of the anti-FLT3 mAb 4G8 and control mAb MOPC21, respectively [12,18]. 4G8-SDIE slightly differs from 4G8-SDIEM (FLYSYN) by the fact that it does not contain an M-tag.…”

“…We have recently introduced mAb and antibody-related constructs carrying the SDIE modification for immunotherapy of different leukemic and solid tumor entities [12][13][14][15][16][17][18]. The most advanced of our compounds is an Fc-optimized mAb, which targets FMS-like tyrosine kinase 3 (FLT3) expressed on the cell surface of leukemic cells in the vast majority of patients with acute myeloid leukemia (AML).…”