Claudin-18.2 as a therapeutic target in cancers: cumulative findings from basic research and clinical trials

Figures & data

Figure 1. Amino acid sequences of claudin-18.1 and claudin-18.2.

These sequences were obtained from the protein knowledgebase (UniProtKB: https://www.uniprot.org/). Red characters show the difference in sequence between claudin-18.1 and −18.2; boxes indicate transmembrane domains.

Figure 2. Claudin-18.2 expression in gastric cancer.

Hematoxylin and eosin staining (A, C) and claudin-18.2 immunohistochemical staining (B, D) of intestinal-type gastric cancer (A, B) and diffuse-type gastric cancer (C, D). Bar, 100 μm.

Table 1. Phase II and III clinical trials with results using zolbetuximab and CAR T cells (accessed on 29 March, 2021)

Name	Date	Phase	Patients	Status of claudin-18.2^a	Line	Clone	Experimental arm	Control arm	Regions	Main result	Identification
MONO^Citation45	2010–2015	II	Claudin-18.2 + G/GEJ/E cancer, metastatic or refractory or recurrent	≥50%	≥2nd	an anti-claudin-18.2 rabbit antiserum	Zolbetuximab	-	Europe^c	ORR: 9% mDOS: 24.6 week	NCT01197885
FAST^Citation50	2012–2019	II	Claudin-18.2+/HER2–G/GEJ/E cancer, unresectable or R2 after resection or recurrent or metastatic	≥40%	1st	CLAUDETECT. ™18.2	EOX + Zolbetuximab	EOX	Europe^d	mPFS^b: 7.5 vs 5.3 mo; OS^b: 13.2 vs 8.4 mo; ORR^b: 39 vs 25%	NCT01630083
ILUSTRO^Citation7	2018-	II	Claudin-18.2 + G/GEJ cancer, unresectable or metastatic (Cohort 3B: PD-L1+)	≥75% (Cohort 3A) and ≥50% (Cohorts 1A, 2 and 3B)	≥3rd (Cohorts 1A and 3A), 1st(Cohorts 2), 3rd (Cohort 3B)	Not listed	Cohort1A:Zolbetuximab, Cohort2: mFOLFOX6 + Zolbetuximab, Cohort 3A/3B: Pembrolizumab + Zolbetuximab	-	Europe, Asia, and North America^e	-	NCT03505320
SPOTLIGHT^Citation8	2018-	III	Claudin-18.2+/HER2 – G/GEJ cancer, unresectable or metastatic	≥75%	1st	Not listed	Zolbetuximab + mFOLFOX6	placebo +mFOLFOX6	North America, Latin America, Europe, Asia, Middle East^f	-	NCT03504397
GLOW^Citation9	2018-	III	Claudin-18.2+/HER2 – G/GEJ cancer, unresectable or metastatic	≥75%	1st	Not listed	Zolbetuximab + CAPOX	Placebo +CAPOX	North America, Latin America, Europe, Asia, Middle East^g	-	NCT03653507
A Study to Assess the Antitumor Activity and Safety of IMAB362 in Combination With Nab-Paclitaxel and Gemcitabine (Nab-P + GEM) as First Line Treatment in Subjects With Claudin 18.2 (CLDN18.2) Positive, Metastatic Pancreatic Adenocarcinoma^Citation51	2019-	II	Claudin-18.2+ Metastatic Pancreatic Adenocarcinoma	≥75%	1st	Not listed	Zolbetuximab + nab-paclitaxel + gemcitabine	nab-paclitaxel +gemcitabine	North America, Europe, and Asia^h	-	NCT03816163
Study to Evaluate the Efficacy, Safety and Pharmacokinetics of CT041 Autologous CAR T-cell Injection	2020-	I/II	Claudin-18.2+ advanced G/GEJ and pancreatic adenocarcinoma	positive on IHC staining	G/GEJ ca.: ≥3rd, pancreatic ca. ≥2nd	Not listed	CT041 autologous CAR T-cell injection	-	Asia^i	-	NCT04581473

EOX: Epirubicin + Oxaliplatin + Capecitabine, CAPOX: Capecitabine + Oxaliplatin

OS, overall survival; mPFS, median progression-free survival; ORR, objective response rate, mDOS: median duration of response, mo: months

^awith moderate-to-strong membranous staining

^bstatistically significant

^cBulgaria, Germany, Latvia, Lithuania, and Switzerland

^dBulgaria, Czechia, Germany, Latvia, Russian Federation, Ukraine

^eUnited States, France, Italy, Japan, Republic of Korea, and Taiwan

^fAustralia, Belgium, Brazil, Canada, Chile, China, Colombia, France, Germany, Israel, Italy, Japan, Republic of Korea, Mexico, Peru, Poland, Spain, Taiwan, United Kingdom, United States

^gArgentina, Austria, Canada, China, Croatia, Greece, Ireland, Japan, Republic of Korea, Malaysia, Netherlands, Portugal, Romania, Spain, Taiwan, Thailand, Turkey, United Kingdom, United States

^hUnited States, Australia, France, Ireland, Italy, Spain, Japan, Republic of Korea, and Taiwan

ⁱChina

Figure 3. Action of zolbetuximab on claudin-18.2 of cancer cells.

In normal epithelial cells, tight junction molecules are complexed and expressed on the apical side, making it difficult for zolbetuximab to bind to claudin-18.2. In contrast, claudin-18.2 is overexpressed in cancer cells and is also expressed on the basolateral side, suggesting that zolbetuximab binds easily to claudin-18.2 in cancer cells. Zolbetuximab shows a cytotoxic effect through the action of antibody-dependent cell-mediatedcytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).

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