Theranostics Vol. 16 - Issue 4 - Research Paper - A novel TM4SF4-targeting therapeutic antibody candidate with antitumor activity by blocking IGF1R and CD44 signaling and downregulating PD-L1 and B7-H4

Sep 23, 2026

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TM4SF4 is highlighted as a key regulator of EMT-associated stemness in non-small cell lung cancer through autocrine IGF1/OPN signaling, making it a promising therapeutic target. An anti-TM4SF4 monoclonal antibody was developed by immunizing mice against the large extracellular loop using a human 15-mer peptide, yielding 2B7, then humanized and affinity-matured to Hz2B7-1.2. The study shows tumor control in xenografts and PDX models via blockade of oncogenic pathways, reduced stemness and therapy resistance, and downregulation of PD-L1 and B7-H4.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages20

Reading Time50 min

AccessFree to download

Abstract

Rationale

Methods

Results

Conclusions

Introduction

Background on NSCLC and therapy resistance

Role of immune checkpoint inhibitors and resistance

Theranostics 2026, Vol. 16, Issue 4 1762 Ivyspring International Publisher Theranostics 2026; 16(4): 1762-1781. doi: 10.7150/thno.113347 Research Paper A novel TM4SF4-targeting therapeutic antibody candidate with antitumor activity by blocking IGF1R and CD44 signaling and downregulating PD-L1 and B7-H4 Rae-Kwon Kim1,2*, Chang-Kyu Heo3*, Mun Ju Choi4*, Yeon-jee Kahm1,5, Min Kyu Kim4, Minyong Lee4, Ji Yoon Lee4, Hwangseo Park4 , Uhee Jung1, Byung-Chul Shin1, Bum-Jin Kim6, Sung-Chul Kim6, Eun-Wie Cho3􀀍, Chun Jeih Ryu4􀀍, In-Gyu Kim1,5􀀍 1. Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute (KAERI), Daejeon 34057, Republic of Korea. 2. Department of Biotechnology, Yong In University, 134, Yongindaehak-ro, Cheoin-gu, Yongin-si, Gyeonggi-do, 17092, Republic of Korea. 3. Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea. 4. Department of Integrative Bioscience and Biotechnology, Institute of Bioscience, Institute of anticancer medicine development, Sejong University, Seoul 05006, Republic of Korea. 5. Department of Radiation Life Science, Korea University of Science and Technology (UST), Daejeon 34113, Republic of Korea. 6. Algok Bio Inc. 320 120th Ave. NE \#208 Bellevue, WA 98005, USA. * Rae-Kwon Kim, Chang-Kyu Heo, and Mun Ju Choi contributed equally to this manuscript and have the same first authority. 􀀍 Corresponding authors: Eun-Wie Cho, Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea, Phone: +82-42-860-4155, E-mail: [ewcho@kribb.re.kr](ewcho@kribb.re.kr); Chun Jeih Ryu, Department of Integrative Bioscience and Biotechnology, Sejong University, 209 Neungdong-ro, Gwangjin-gu, Seoul 05006, Republic of Korea, Phone: +82-2-3408-3718, [E-mail: cjryu@sejong.ac.kr](E-mail: cjryu@sejong.ac.kr); In-Gyu Kim, Department of Radiation Life Science, Korea University of Science and Technology (UST), Daejeon 34113, Republic of Korea. + 82-42-868-8030, E-mail: [igkim@ust.ac.kr](igkim@ust.ac.kr). © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). See [https://ivyspring.com/terms](https://ivyspring.com/terms) for full terms and conditions. Received: 2025.03.06; Accepted: 2025.10.28; Published: 2026.01.01 Abstract Rationale: Transmembrane 4 superfamily member 4 (TM4SF4) has been identified as a key regulator of epithelial-mesenchymal transition (EMT)-associated stemness in non-small cell lung cancer (NSCLC) cells through autocrine signaling involving insulin-like growth factor 1 (IGF1) and osteopontin (OPN). Given its pivotal role in tumor progression and therapy resistance, TM4SF4 represents a promising therapeutic target. Methods: To develop a therapeutic antibody against TM4SF4, we generated anti-TM4SF4 monoclonal antibodies in mice by targeting the large extracellular loop (LEL) of human TM4SF4 using a 15-mer peptide, hTM4SF4 (T126–E140). Among the generated clones, the 2B7 antibody exhibited high specificity and reactivity to TM4SF4. Mechanistic studies were conducted to evaluate the effects of 2B7 on key signaling pathways, EMT-associated stemness, immune checkpoint ligand (ICL) expression, and immune responses. To facilitate clinical translation, 2B7 was humanized, generating the Hz2B7-1.1 antibody, which underwent affinity maturation to select the lead candidate, Hz2B7-1.2. Functional assays, including antibody-dependent cellular cytotoxicity (ADCC) and preclinical evaluations in xenograft models, were performed to assess its therapeutic potential. Results: The 2B7 antibody demonstrated significant antitumor efficacy in both A549 xenograft and patient-derived xenograft (PDX) models. Mechanist

FAQs

What role does TM4SF4 play in non-small cell lung cancer in this study?

TM4SF4 is described as a key regulator of EMT-associated stemness in NSCLC cells via autocrine signaling involving IGF1 and osteopontin, contributing to tumor progression and therapy resistance.

How was the TM4SF4-targeting antibody candidate developed?

Anti-TM4SF4 monoclonal antibodies were generated by targeting the large extracellular loop of human TM4SF4 using a 15-mer peptide, hTM4SF4 (T126–E140). The 2B7 clone was then humanized and affinity-matured to obtain Hz2B7-1.2 as the lead candidate.

What mechanisms explain the antitumor activity of Hz2B7-1.2?

Hz2B7-1.2 inhibits major signaling pathways (PI3K/AKT/GSK3β/β-catenin and JAK2/STAT3), reduces EMT-associated stemness and therapy resistance, downregulates immune checkpoint ligands PD-L1 and B7-H4, and supports antitumor immune responses including ADCC as an IgG1-type antibody.

Sep 23, 2026

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