Antibodies Targeting the Transferrin Receptor 1 (TfR1) as Direct Anti-cancer Agents

Abstract

The transferrin receptor 1 (TfR1), also known as cluster of differentiation 71 (CD71), is a type II transmembrane glycoprotein that binds transferrin (Tf) and performs a critical role in cellular iron uptake through the interaction with iron-bound Tf. Iron is required for multiple cellular processes and is essential for DNA synthesis and, thus, cellular proliferation. Due to its central role in cancer cell pathology, malignant cells often overexpress TfR1 and this increased expression can be associated with poor prognosis in different types of cancer. The elevated levels of TfR1 expression on malignant cells, together with its extracellular accessibility, ability to internalize, and central role in cancer cell pathology make this receptor an attractive target for antibody-mediated therapy. The TfR1 can be targeted by antibodies for cancer therapy in two distinct ways: (1) indirectly through the use of antibodies conjugated to anti-cancer agents that are internalized by receptor-mediated endocytosis or (2) directly through the use of antibodies that disrupt the function of the receptor and/or induce Fc effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC). Although TfR1 has been used extensively as a target for antibody-mediated cancer therapy over the years, interest continues to increase for both targeting the receptor for delivery purposes and for its use as direct anti-cancer agents. This review focuses on the developments in the use of antibodies targeting TfR1 as direct anti-tumor agents.

Integrated analysis identifies TfR1 as a prognostic biomarker which correlates with immune infiltration in breast cancer

“…TfR1 has been explored as a potential therapeutic target due to its cell surface accessibility, constitutive endocytosis into cells, requirement for cell growth, and overexpression by cancer cells [ 13 ]. Among the developed therapeutic treatments targeting TfR1, antibodies stand out because of their exquisite specificity and high affinity [ 14 , 15 , 44 ]. TfR1 monoclonal antibodies, including 42/6, A24, JST-TFR09, and ch128.1Av (anti-hTfR1 IgG3-Av), facilitate the accumulation of nonselective therapeutic agents in cancer cells, elevate the intracellular drug concentration, improve anticancer activity, and enhance therapeutic efficacy [ 14 , 15 ].…”

Nrf2 Is a Potential Modulator for Orchestrating Iron Homeostasis and Redox Balance in Cancer Cells

“…TfR1 is a candidate marker of poor prognosis in breast cancer ( Habashy et al, 2010 ). Therefore, TfR1 is a promising target in treating the cancers with overexpressed TfR1 and increased iron demands ( Candelaria et al, 2021 ). Anti-TfR1 antibodies have been demonstrated to be an efficient therapy for leukemias and lymphomas ( Neiveyans et al, 2019 ).…”

Developing Actively Targeted Nanoparticles to Fight Cancer: Focus on Italian Research

“…It has been shown that TfRs are overexpressed, 2–10-fold, in most tumor cells, including breast, lung, brain, liver, ovarian prostate and colon cancer cells, and are directly involved in the process of iron homeostasis and cell proliferation, making them attractive and effective targets for site-specific antitumor drug delivery [ 41 ]. TfRs are therefore interesting targets in the development of ligand-based nanotherapies that involve the natural ligand Tf, mAbs or single-chain variable fragments (scFv) [ 42 , 43 ]. The Tf approach has been most thoroughly investigated for drug delivery to the brain, as the Tf ligand facilitates transcytosis of the conjugated drug-carrier systems across the blood brain barrier (BBB).…”