Antitumor activities of anti‑CD44 monoclonal antibodies in mouse xenograft models of esophageal cancer

Ishikawa,Kenichiro; Suzuki,Hiroyuki; Ohishi,Tomokazu; Nakamura,Takuro; Yanaka,Miyuki; Li,Guanjie; Tanaka,Tomohiro; Ohkoshi,Akira; Kawada,Manabu; Kaneko,Mika K.; Katori,Yukio; Kato,Yukinari

doi:10.3892/or.2024.8806

Antitumor activities of anti‑CD44 monoclonal antibodies in mouse xenograft models of esophageal cancer

Authors:
- Kenichiro Ishikawa
- Hiroyuki Suzuki
- Tomokazu Ohishi
- Takuro Nakamura
- Miyuki Yanaka
- Guanjie Li
- Tomohiro Tanaka
- Akira Ohkoshi
- Manabu Kawada
- Mika K. Kaneko
- Yukio Katori
- Yukinari Kato
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Affiliations: Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Aoba‑ku, Sendai, Miyagi 980‑8575, Japan, Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu, Shizuoka 410‑0301, Japan, Department of Otolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, Aoba‑ku, Sendai, Miyagi 980‑8575, Japan, Institute of Microbial Chemistry (BIKAKEN), Laboratory of Oncology, Microbial Chemistry Research Foundation, Shinagawa‑ku, Tokyo 141‑0021, Japan
Published online on: August 29, 2024 https://doi.org/10.3892/or.2024.8806
Article Number: 147
Copyright: © Ishikawa et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

CD44 is a type I transmembrane glycoprotein associated with poor prognosis in various solid tumors. Since CD44 plays a critical role in tumor development by regulating cell adhesion, survival, proliferation and stemness, it has been considered a target for tumor therapy. Anti‑CD44 monoclonal antibodies (mAbs) have been developed and applied to antibody‑drug conjugates and chimeric antigen receptor‑T cell therapy. Anti-pan‑CD44 mAbs, C₄₄Mab‑5 and C₄₄Mab‑46, which recognize both CD44 standard (CD44s) and variant isoforms were previously developed. The present study generated a mouse IgG_2a version of the anti‑pan‑CD44 mAbs (5‑mG_2a and C₄₄Mab‑46‑mG_2a) to evaluate the antitumor activities against CD44‑positive cells. Both 5‑mG_2a and C₄₄Mab‑46‑mG_2a recognized CD44s‑overexpressed CHO‑K1 (CHO/CD44s) cells and esophageal tumor cell line (KYSE770) in flow cytometry. Furthermore, both 5‑mG_2a and C₄₄Mab‑46‑mG_2a could activate effector cells in the presence of CHO/CD44s cells and exhibited complement-dependent cytotoxicity against both CHO/CD44s and KYSE770 cells. Furthermore, the administration of 5‑mG_2a and C₄₄Mab‑46‑mG_2a significantly suppressed CHO/CD44s and KYSE770 xenograft tumor development compared with the control mouse IgG_2a. These results indicate that 5‑mG_2a and C₄₄Mab‑46‑mG_2a could exert antitumor activities against CD44‑positive cancers and be a promising therapeutic regimen for tumors.

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1	Ponta H, Sherman L and Herrlich PA: CD44: From adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol. 4:33–45. 2003. View Article : Google Scholar : PubMed/NCBI
2	Zöller M: CD44: Can a cancer-initiating cell profit from an abundantly expressed molecule? Nat Rev Cancer. 11:254–267. 2011. View Article : Google Scholar : PubMed/NCBI
3	Prochazka L, Tesarik R and Turanek J: Regulation of alternative splicing of CD44 in cancer. Cell Signal. 26:2234–2239. 2014. View Article : Google Scholar : PubMed/NCBI
4	Guo Q, Yang C and Gao F: The state of CD44 activation in cancer progression and therapeutic targeting. FEBS J. 289:7970–7986. 2022. View Article : Google Scholar : PubMed/NCBI
5	Zöller M: CD44, hyaluronan, the hematopoietic stem cell, and leukemia-initiating cells. Front Immunol. 6:2352015.PubMed/NCBI
6	Hassn Mesrati M, Syafruddin SE, Mohtar MA and Syahir A: CD44: A multifunctional mediator of cancer progression. Biomolecules. 11:18502021. View Article : Google Scholar : PubMed/NCBI
7	Cirillo N: The hyaluronan/CD44 axis: A double-edged sword in cancer. Int J Mol Sci. 24:158122023. View Article : Google Scholar : PubMed/NCBI
8	Liu Y, Wu T, Lu D, Zhen J and Zhang L: CD44 overexpression related to lymph node metastasis and poor prognosis of pancreatic cancer. Int J Biol Markers. 33:308–313. 2018. View Article : Google Scholar : PubMed/NCBI
9	Tao Y, Li H, Huang R, Mo D, Zeng T, Fang M and Li M: Clinicopathological and prognostic significance of cancer stem cell markers in ovarian cancer patients: Evidence from 52 studies. Cell Physiol Biochem. 46:1716–1726. 2018. View Article : Google Scholar : PubMed/NCBI
10	Li L, Hao X, Qin J, Tang W, He F, Smith A, Zhang M, Simeone DM, Qiao XT, Chen ZN, et al: Antibody against CD44s inhibits pancreatic tumor initiation and postradiation recurrence in mice. Gastroenterology. 146:1108–1118. 2014. View Article : Google Scholar : PubMed/NCBI
11	Zhang S, Wu CC, Fecteau JF, Cui B, Chen L, Zhang L, Wu R, Rassenti L, Lao F, Weigand S and Kipps TJ: Targeting chronic lymphocytic leukemia cells with a humanized monoclonal antibody specific for CD44. Proc Natl Acad Sci USA. 110:6127–6132. 2013. View Article : Google Scholar : PubMed/NCBI
12	Vey N, Delaunay J, Martinelli G, Fiedler W, Raffoux E, Prebet T, Gomez-Roca C, Papayannidis C, Kebenko M, Paschka P, et al: Phase I clinical study of RG7356, an anti-CD44 humanized antibody, in patients with acute myeloid leukemia. Oncotarget. 7:32532–32542. 2016. View Article : Google Scholar : PubMed/NCBI
13	Menke-van der Houven van Oordt CW, Gomez-Roca C, van Herpen C, Coveler AL, Mahalingam D, Verheul HM, van der Graaf WT, Christen R, Rüttinger D, Weigand S, et al: First-in-human phase I clinical trial of RG7356, an anti-CD44 humanized antibody, in patients with advanced, CD44-expressing solid tumors. Oncotarget. 7:80046–80058. 2016. View Article : Google Scholar : PubMed/NCBI
14	Todaro M, Gaggianesi M, Catalano V, Benfante A, Iovino F, Biffoni M, Apuzzo T, Sperduti I, Volpe S, Cocorullo G, et al: CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. Cell Stem Cell. 14:342–356. 2014. View Article : Google Scholar : PubMed/NCBI
15	Verel I, Heider KH, Siegmund M, Ostermann E, Patzelt E, Sproll M, Snow GB, Adolf GR and van Dongen GA: Tumor targeting properties of monoclonal antibodies with different affinity for target antigen CD44V6 in nude mice bearing head-and-neck cancer xenografts. Int J Cancer. 99:396–402. 2002. View Article : Google Scholar : PubMed/NCBI
16	Orian-Rousseau V and Ponta H: Perspectives of CD44 targeting therapies. Arch Toxicol. 89:3–14. 2015. View Article : Google Scholar : PubMed/NCBI
17	Tijink BM, Buter J, de Bree R, Giaccone G, Lang MS, Staab A, Leemans CR and van Dongen GA: A phase I dose escalation study with anti-CD44v6 bivatuzumab mertansine in patients with incurable squamous cell carcinoma of the head and neck or esophagus. Clin Cancer Res. 12:6064–6072. 2006. View Article : Google Scholar : PubMed/NCBI
18	Riechelmann H, Sauter A, Golze W, Hanft G, Schroen C, Hoermann K, Erhardt T and Gronau S: Phase I trial with the CD44v6-targeting immunoconjugate bivatuzumab mertansine in head and neck squamous cell carcinoma. Oral Oncol. 44:823–829. 2008. View Article : Google Scholar : PubMed/NCBI
19	Casucci M, Nicolis di Robilant B, Falcone L, Camisa B, Norelli M, Genovese P, Gentner B, Gullotta F, Ponzoni M, Bernardi M, et al: CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma. Blood. 122:3461–3472. 2013. View Article : Google Scholar : PubMed/NCBI
20	Porcellini S, Asperti C, Corna S, Cicoria E, Valtolina V, Stornaiuolo A, Valentinis B, Bordignon C and Traversari C: CAR T cells redirected to CD44v6 control tumor growth in lung and ovary adenocarcinoma bearing mice. Front Immunol. 11:992020. View Article : Google Scholar : PubMed/NCBI
21	Yamada S, Itai S, Nakamura T, Yanaka M, Kaneko MK and Kato Y: Detection of high CD44 expression in oral cancers using the novel monoclonal antibody, C₄₄Mab-5. Biochem Biophys Rep. 14:64–68. 2018.PubMed/NCBI
22	Goto N, Suzuki H, Tanaka T, Asano T, Kaneko MK and Kato Y: Development of a novel Anti-CD44 monoclonal antibody for multiple applications against esophageal squamous cell carcinomas. Int J Mol Sci. 23:55352022. View Article : Google Scholar : PubMed/NCBI
23	Takei J, Asano T, Suzuki H, Kaneko MK and Kato Y: Epitope mapping of the anti-CD44 monoclonal antibody (C44Mab-46) using alanine-scanning mutagenesis and surface plasmon resonance. Monoclon Antib Immunodiagn Immunother. 40:219–226. 2021. View Article : Google Scholar : PubMed/NCBI
24	Asano T, Kaneko MK, Takei J, Tateyama N and Kato Y: Epitope mapping of the anti-CD44 monoclonal antibody (C₄₄Mab-46) using the REMAP method. Monoclon Antib Immunodiagn Immunother. 40:156–161. 2021. View Article : Google Scholar : PubMed/NCBI
25	Asano T, Kaneko MK and Kato Y: Development of a novel epitope mapping system: RIEDL insertion for epitope mapping method. Monoclon Antib Immunodiagn Immunother. 40:162–167. 2021. View Article : Google Scholar : PubMed/NCBI
26	Suzuki H, Kitamura K, Goto N, Ishikawa K, Ouchida T, Tanaka T, Kaneko MK and Kato Y: A Novel anti-CD44 variant 3 monoclonal antibody C₄₄Mab-6 was established for multiple applications. Int J Mol Sci. 24:84112023. View Article : Google Scholar : PubMed/NCBI
27	Suzuki H, Tanaka T, Goto N, Kaneko MK and Kato Y: Development of a novel anti-CD44 variant 4 monoclonal antibody C₄₄Mab-108 for immunohistochemistry. Curr Issues Mol Biol. 45:1875–1888. 2023. View Article : Google Scholar : PubMed/NCBI
28	Kudo Y, Suzuki H, Tanaka T, Kaneko MK and Kato Y: Development of a novel Anti-CD44 variant 5 monoclonal antibody C₄₄Mab-3 for multiple applications against pancreatic carcinomas. Antibodies (Basel). 12:312023. View Article : Google Scholar : PubMed/NCBI
29	Ejima R, Suzuki H, Tanaka T, Asano T, Kaneko MK and Kato Y: Development of a novel Anti-CD44 variant 6 monoclonal antibody C₄₄Mab-9 for multiple applications against colorectal carcinomas. Int J Mol Sci. 24:40072023. View Article : Google Scholar : PubMed/NCBI
30	Suzuki H, Ozawa K, Tanaka T, Kaneko MK and Kato Y: Development of a novel anti-CD44 variant 7/8 monoclonal antibody, C₄₄Mab-34, for multiple applications against oral carcinomas. Biomedicines. 11:10992023. View Article : Google Scholar : PubMed/NCBI
31	Tawara M, Suzuki H, Goto N, Tanaka T, Kaneko MK and Kato Y: A novel anti-CD44 variant 9 monoclonal antibody C₄₄Mab-1 was developed for immunohistochemical analyses against colorectal cancers. Curr Issues Mol Biol. 45:3658–3673. 2023. View Article : Google Scholar : PubMed/NCBI
32	Ishikawa K, Suzuki H, Kaneko MK and Kato Y: Establishment of a novel anti-CD44 variant 10 monoclonal antibody C₄₄Mab-18 for immunohistochemical analysis against oral squamous cell carcinomas. Curr Issues Mol Biol. 45:5248–5262. 2023. View Article : Google Scholar : PubMed/NCBI
33	Li G, Suzuki H, Ohishi T, Asano T, Tanaka T, Yanaka M, Nakamura T, Yoshikawa T, Kawada M, Kaneko MK and Kato Y: Antitumor activities of a defucosylated anti-EpCAM monoclonal antibody in colorectal carcinoma xenograft models. Int J Mol Med. 51:182023. View Article : Google Scholar : PubMed/NCBI
34	Nanamiya R, Suzuki H, Takei J, Li G, Goto N, Harada H, Saito M, Tanaka T, Asano T, Kaneko MK and Kato Y: Development of monoclonal antibody 281-mG_2a-f against golden hamster podoplanin. Monoclon Antib Immunodiagn Immunother. 41:311–319. 2022. View Article : Google Scholar : PubMed/NCBI
35	Queiroz AL, Dantas E, Ramsamooj S, Murthy A, Ahmed M, Zunica ERM, Liang RJ, Murphy J, Holman CD, Bare CJ, et al: Blocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer. Nat Commun. 13:46332022. View Article : Google Scholar : PubMed/NCBI
36	Yamada S, Kaneko MK, Nakamura T, Ichii O, Konnai S and Kato Y: Development of mPMab-1, a mouse-rat chimeric antibody against mouse podoplanin. Monoclon Antib Immunodiagn Immunother. 36:77–79. 2017. View Article : Google Scholar : PubMed/NCBI
37	Garvin D, Stecha P, Gilden J, Wang J, Grailer J, Hartnett J, Fan F, Cong M and Cheng ZJ: Determining ADCC activity of antibody-based therapeutic molecules using two bioluminescent reporter-based bioassays. Curr Protoc. 1:e2962021. View Article : Google Scholar : PubMed/NCBI
38	Takei J, Kaneko MK, Ohishi T, Hosono H, Nakamura T, Yanaka M, Sano M, Asano T, Sayama Y, Kawada M, et al: A defucosylated anti-CD44 monoclonal antibody 5-mG2a-f exerts antitumor effects in mouse xenograft models of oral squamous cell carcinoma. Oncol Rep. 44:1949–1960. 2020.PubMed/NCBI
39	Birzele F, Voss E, Nopora A, Honold K, Heil F, Lohmann S, Verheul H, Le Tourneau C, Delord JP, van Herpen C, et al: CD44 isoform status predicts response to treatment with anti-CD44 antibody in cancer patients. Clin Cancer Res. 21:2753–2762. 2015. View Article : Google Scholar : PubMed/NCBI
40	Golay J and Taylor RP: The role of complement in the mechanism of action of therapeutic anti-cancer mAbs. Antibodies (Basel). 9:582020. View Article : Google Scholar : PubMed/NCBI
41	Reis ES, Mastellos DC, Ricklin D, Mantovani A and Lambris JD: Complement in cancer: Untangling an intricate relationship. Nat Rev Immunol. 18:5–18. 2018. View Article : Google Scholar : PubMed/NCBI
42	Galon J and Bruni D: Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat Rev Drug Discov. 18:197–218. 2019. View Article : Google Scholar : PubMed/NCBI
43	Hiemstra IH, Santegoets KCM, Janmaat ML, De Goeij BECG, Ten Hagen W, van Dooremalen S, Boross P, van den Brakel J, Bosgra S, Andringa G, et al: Preclinical anti-tumour activity of HexaBody-CD38, a next-generation CD38 antibody with superior complement-dependent cytotoxic activity. EBioMedicine. 93:1046632023. View Article : Google Scholar : PubMed/NCBI
44	de Jong RN, Beurskens FJ, Verploegen S, Strumane K, van Kampen MD, Voorhorst M, Horstman W, Engelberts PJ, Oostindie SC, Wang G, et al: A novel platform for the potentiation of therapeutic antibodies based on antigen-dependent formation of IgG hexamers at the cell surface. PLoS Biol. 14:e10023442016. View Article : Google Scholar : PubMed/NCBI
45	Schmudde I, Laumonnier Y and Köhl J: Anaphylatoxins coordinate innate and adaptive immune responses in allergic asthma. Semin Immunol. 25:2–11. 2013. View Article : Google Scholar : PubMed/NCBI
46	Carroll MC and Isenman DE: Regulation of humoral immunity by complement. Immunity. 37:199–207. 2012. View Article : Google Scholar : PubMed/NCBI
47	Gogia P, Ashraf H, Bhasin S and Xu Y: Antibody-drug conjugates: A review of approved drugs and their clinical level of evidence. Cancers (Basel). 15:38862023. View Article : Google Scholar : PubMed/NCBI
48	Arimori T, Mihara E, Suzuki H, Ohishi T, Tanaka T, Kaneko MK, Takagi J and Kato Y: Locally misfolded HER2 expressed on cancer cells is a promising target for development of cancer-specific antibodies. Structure. 32:536–549.e5. 2024. View Article : Google Scholar : PubMed/NCBI
49	Kaneko MK, Suzuki H and Kato Y: Establishment of a novel cancer-specific anti-HER₂ monoclonal antibody H₂Mab-250/H₂CasMab-2 for breast cancers. Monoclon Antib Immunodiagn Immunother. 43:35–43. 2024. View Article : Google Scholar : PubMed/NCBI
50	Kaneko MK, Suzuki H, Ohishi T, Nakamura T, Tanaka T and Kato Y: A cancer-specific monoclonal antibody against HER2 exerts antitumor activities in human breast cancer xenograft models. Int J Mol Sci. 25:19412024. View Article : Google Scholar : PubMed/NCBI
51	Lodewijk I, Dueñas M, Paramio JM and Rubio C: CD44v6, STn & O-GD2: Promising tumor associated antigens paving the way for new targeted cancer therapies. Front Immunol. 14:12726812023. View Article : Google Scholar : PubMed/NCBI
52	Aasted MKM, Groen AC, Keane JT, Dabelsteen S, Tan E, Schnabel J, Liu F, Lewis HS, Theodoropulos C, Posey AD and Wandall HH: Targeting solid cancers with a cancer-specific monoclonal antibody to surface expressed aberrantly O-glycosylated proteins. Mol Cancer Ther. 22:1204–1214. 2023. View Article : Google Scholar : PubMed/NCBI