Carbonic anhydrases are metalloenzymes that reversibly catalyze the hydration of carbon dioxide, generating bicarbonate ions and protons. Several tumors, such as clear cell renal cell carcinoma (ccRCC), glioblastoma, triple-negative breast cancer, ovarian cancer, colorectal, and others overexpress carbonic anhydrase isoform IX (CAIX). The CAIX enzyme is constitutively overexpressed in the vast majority of clear cell renal cell carcinoma (ccRCC) and can also be induced in hypoxic microenvironments, a major hallmark of most solid tumors. CAIX expression is restricted to a few sites in healthy tissues, positioning this molecule as a strategic target for cancer immunotherapy.
Author | Antibody Type | Tumor Type | Dosage | Response | ||||||||||
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mIL2-XE114-mTNFmut: 50% | ||||||||||||||
Author | Phase | Treatment | Clinical Response | Adverse Effects (≥3 Grade) | ||||||||||||||||||||||||||||||||||
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Surfus et al. (1996) [17] | cG250 | |||||||||||||||||||||||||||||||||||||
Divgi et al. (1998) [14] | I/II | RCC and breast carcinoma cell lines | mG250 (10 mg single i.v. infusion) combined with 131I (30, 45, 60, 75, and 90 mCi/m2) | cG250: 0.5 µg/mL, | IL2: 100 U/mL | ADCC with PBMCs (effector to target rate 100:1) after 4 h | RCC—SK-RC-13: cG250 48%; cG250 + IL2 50%; | SK-RC-30: cG250 25%; cG250 + IL2 65%; | Breast cancer—BT-20: cG250 38%; cG250 + IL2 28% | |||||||||||||||||||||||||||||
1/33 CR; 17/33 SD—2 months after treatment | 19/33 grade 3 (thrombocytopenia, hematotoxicity, hepatoxicity); 3/33 grade 4 (thrombocytopenia and hematotoxicity); 33/33 HAMA | Liu et al. (2002) [18] | cG250 | |||||||||||||||||||||||||||||||||||
Steffens et al. (1999) [29] | RCC and chronic myelogenous leukemia | I | cG250: 1 µg/mL, IL2 10 IU/mL; |
cG250 (5 mg single i.v. infusion) combined with 131 | IFNγ, IFN-2a, IFN-2b 1000 IU/mL | l (222–2775 MBq/m2) | 6/12 PD; 1/12 SD—lasting 3–6 months; 1/12 PR—9 months or longer | ADCC with PBMC (effector to target rate 25:1) after 2 days | RCC—SK-RC-52: cG250 + IL2 42%; cG250 + IFN-? 33%; cG250 + IFN-?-2a or cG250 + IFN-α-2b 25%; | SK-RC-09: cG250 + IL2 28%; cG250 + IFN-?; cG250 + IFN-?-2a, and cG250 + IFN-α-2b < 10%; | Leukemia—K562: cG250 + IL2 60%; cG250 + IFN-? 30%; cG250 + IFN-?-2a or cG250 + INF-α-2b 43% | |||||||||||||||||||||||||||
1/12 grade 3 (leukocytopenia); 2/12 grade 4 (thrombocytopenia and leukocytopenia); 1/12 HACA | Brouwers et al. (2004) [19] | |||||||||||||||||||||||||||||||||||||
Bleumer et al. (2004) [30] | 131I-cG250, 90Y-SCN-Bz- DTPA-cG250, 177Lu-SCN-Bz-DTPA-cG250, or 186Re-MAG3 cG250 | II | RCC | cG250 (25 mg/m2 weekly i.v. infusion for 12 weeks) | 30 µg 131I-cG250, | 30 µg |
10/36 SD, 17/36 PD—week 16; 8/36 SD—week 24; 1/36 CR, 1/36 PR—week 38–44 90Y-SCN-Bz-DTPA-cG250, | 60 µg 177 Lu-SCN-Bz-DTPA-cG250, or | 35 µg 186 Re-MAG3-cG250; | Variable doses of radioisotopes | Best median survival (SK-RC-52 cells) | 177 Lu-SCN-Bz-DTPA cG250: 294 days; | 90 Y-SCN-Bz-DTPA cG250: 241 days; | 186 Re-MAG3-cG250: 211 days; | 131 I-cG250: 164 days; | Control groups < 150 days | ||||||||||||||||||||||
* 33/36 grade 3 (pain, pulmonary, cardiovascular, constitutional symptoms, neurological, bone marrow, genitourinary, hemorrhage, hepatic, metabolic/laboratory); 5/36 grade 4 (pulmonary, hemorrhage) | Bauer et al. (2009) [20] | cG250-TNF and cG250 | RCC | 100 µg of cG250 or cG250-TNF | ||||||||||||||||||||||||||||||||||
Bleumer et al. (2006) [31] | III | 300 ng every 3 days | cG250 (20 mg by i.v. infusion for 11 weeks) combined with IL2 (1.8–5.4 MIU daily for 12 consecutive weeks) | In vivo tumor size after 78 days (SK-RC-52 cells) | 1/35 PR, 11/35 SD, 23/35 PD—week 16; 1/35 PR, 7/35 SD, 4/35 PD—week 22 cG250-TNF + IFNγ: 60% decrease; | cG250-TNF: 50% decrease; | cG250 + IFNγ: no difference in tumor size | compared to negative control | ||||||||||||||||||||||||||||||
17/35 grade 3 (constitutional symptoms, pain, pulmonary, blood/bone marrow, hepatic); 2/35 grade 4 (renal/genitourinary and metabolic/laboratory); 2/36 HACA | Zatovicova et al. (2010) [21] | VII/20 | ||||||||||||||||||||||||||||||||||||
Davis et al. (2007) [32] | Pilot | Colorectal carcinoma | cG250 (10 mg/m2/week, first and fifth doses trace-labeled with 131I) and 1.25 × 106 IU/m2/day IL2 for six weeks | 100 μg twice a week | 2/9 SD, 7/9 PD—after six-week cycle 1; 1/9 SD, 1/9 PD—after six-week cycle 2 | In vivo tumor weight/volume reduction (HT-29 cells) | 60%/73% treatment initiated | after 10 days of tumor implantation; | 88%/93% treatment initiated | in the same day of tumor implantation | ||||||||||||||||||||||||||||
* 3/9 grade 3 or 4 (dyspnea and anemia) | Oosterwijk-Wakka et al. (2011) [22] | 125 | ||||||||||||||||||||||||||||||||||||
Davis et al. (2007) [33]I-cG250 + sorafenib, sunitinib, or vandetanib | RCC | I | cG250 (5, 10, 25, or 50 mg/m2 i.v. for 6 weeks) combined with 131l (200–350 MBq/m2) weeks 1 and 5 | 125I-cG250 185 kBq/5 μg | 35 mg/kg of sunitinib, | 50 mg/kg of sorafenib, | 50 mg/kg of vandetanib | 1/13 CR, 8/13 SD, 3/13 PD—first six-weeks cycle; 1/13 CR, 6/13 SD, 2/13 PD—second six-weeks cycle | In vivo tumor volume (NU-12 cells) decrease for continuous treatment (14 days) | Vandetanib: 57%, sunitinib: 49%, and | sorafenib: 37%, | all compared to 125 |
* 1/13 grade 3 (bone pain), 1/13 HACA I-cG250 alone | |||||||||||||||||||||||||
Petrul et al. (2012) [23] | ||||||||||||||||||||||||||||||||||||||
Siebels et al. (2010) [34] | BAY 79-4620 | I/II | Colorectal cancer, gastric carcinoma, and NSCLC-PDX | cG250 (20 mg i.v. infusion; week 2–12) combined with LD-IFNα (3 MIU s.c. 3 times/week; weeks 1–12) | Variable | In vivo tumor regression (3 doses of every 4 days) | Colorectal cancer (dose 10 mg/kg): HT-29: 100%, Colo205: 85%; | Gastric carcinoma (dose 60 mg/kg): NCI-N87: 87%, MKN-45: 90%, SNU-16: 75%; | NSCLC-PDX: complete regression in 2/5, partial regression in 3/5 | |||||||||||||||||||||||||||||
2/26 PR, 14/26 SD—week 16; 1/26 CR, 9/26 SD—24 weeks or longer | 11/26 grade 3 (constitutional symptoms, pain, pulmonary, musculoskeletal, cardiovascular, secondary malignancy, lymphatics); 1/26 grade 4 (gastrointestinal) | Muselaers et al. (2014) [15] | ||||||||||||||||||||||||||||||||||||
Stillebroer et al. (2013) [35] | 111In-DOTA-mG250 and 177Lu-DOTA-mG250 | RCC | I | cG250 (10 mg i.v. infusion—three consecutive) combined with 131ln (1110–2405 MBq/m2) | 13 MBq 177Lu-DOTA-mG250, | 13 MBq nonspecific 177Lu-DOTA-MOPC21, | 20 MBq 111 In-DOTA-mG250 | 17/23 SD—during the 3 months 1/23 PR—lasted 9 months | Median survival (SK-RC-52 cells) | 177 Lu-DOTA-mG250: 139 days; | 177 Lu-DOTA-MOPC21: 49 days; | 111 In-DOTA-mG250: 53 days; | Control: 49–53 days | |||||||||||||||||||||||||
3/23 grade 4 (myelotoxicity); 4/23 HACA | Zatovicova et al. (2014) [16] | |||||||||||||||||||||||||||||||||||||
Muselaers et al. (2016) [36] | mG250 | II | Colorectal carcinoma | cG250 (10 mg i.v. infusion) combined with 111In (185 MBq/m2); 177Lu (2405 MBq/m2) 9–10 days after infusion; 177 | 100 µg/dose | Lu (1805 MBq/m2) weeks 12–14 | 1/14 PR, 8/14 SD, 5/9 PD—after cycle 1; 1/14 PR, 4/14 SD, 1/14 PD—after cycle 2 | In vivo tumor weight/volume reduction (HT-29 cells) | Treatment initiated after 10 days | of tumor implantation: 55%/73%; | Treatment initiated at the same day | of tumor implantation: 90%/93% | ||||||||||||||||||||||||||
12/14 grade 3–4 (thrombocytopenia); 9/14 grade 3–4 (leukocytopenia); 2/14 grade 3 (fatigue and anorexia); 4/14 grade 4 (neutropenia) | Chang et al. (2015) [24] | In vitro: G10, G36, G37, G39, and G119; | In vivo: only G37 and G119 were tested | RCC | ADCC in vitro: 5 µg/mL, | In vivo: 10 mg/kg | CAIX-TPL-Lips: 90 days (statistically significant compared to saline control); | |||||||||||||||||||||||||||||||
Chamie et al. (2017) [37] | ADCC in SK-RC-09 cells: | 25:1 effector to target cells: 25% for G36 and G119; 15–20% for G10, G37, and G39; | 50:1 effector to target cells: 45% for G10, G36, G37, and G119; 30% for G39 | In vivo tumor weight (Day 29)/volume (Day 28) |
III | cG250 (50 mg i.v.; week 1; 20 mg i.v. weeks 2–24) | reduction (SK-RC-59 CAIX+ cells): | 85%/75% for G37, G119, mG37, and mG119 | ||||||||||||||||||||||||||||||
NR | 72/864 grade 3 or 4—type not mentioned | Oosterwijk-Wakka et al. (2015) [25] | 111In-cG250 and Sunitinib | RCC | 0.4 MBq/5 µg 111In-cG250 three days after administration of 40–50 mg/kg of sunitinib | for 13 days | In vivo tumor growth reduction 20 days after the beginning of the treatment with sunitinib | NU-12: 60%; | SK-RC-52: not statistically significant compared to control | |||||||||||||||||||||||||||||
Yamaguchi et al. (2015) [26] | chKM4927 and chKM4927_N297D | RCC | 10 mg/kg i.p. twice a week for three weeks | In vivo tumor volume (VMRC-RCW cells) | reduction after 32 days | chKM4927 and chKM4927_N297D: | 60% compared to negative control | |||||||||||||||||||||||||||||||
Lin et al. (2017) [27] | Anti-CAIX functionalized liposomes with TPL | Lung cancer cells | 0.15 mg/kg once every 3–4 days for 8 times | via pulmonary | delivery | Median survival time (A549 cells) | Nontargeted TPL-lips: 71 days (not statistically significant compared to saline control); | Control group: 45 days | ||||||||||||||||||||||||||||||
De Luca et al. (2019) [28] | IL2-Anti-CAIX(XE114)-TNFmut and | IL2-Anti-CAIX(F8)-TNFmut | Colon Carcinoma | 30 µg i.v. four times every 24 h | Tumor volume reduction (CT26-CAIX cells) after 18 days | IL2-F8-TNFmut: 58%; | mIL2-F8-mTNFmut: 72%; | IL2-XE114-TNFmut: 63%; |
PD: progressive disease, SD: stable disease, PR: partial response, CR: complete response, MTD: maximum tolerated dose, ND: not detected, NE: not evaluable, NR: no response, HAMA: human antimouse antibodies, HACA: human anti-chimeric antibodies. * All grade 3 and 4 toxicities were not related to the study medication. Doses highlighted in bold are related to clinical responses reported.