In all treated patients, ORR=27.70% (95% CI 17.30% to 40.20%), including one complete (1.50%) and 17 partial responses (26.20%). Mdor=7.60 months (95% CI 3.30 to 10.20), mPFS=5.0 months (95% CI 3.20 to 6.00). In high mesothelin expression patients (N=19), who received 3 prior lines of systemic therapy, ORR=42.10% (95% CI 20.30% to 66.50%), mDOR=8.30 months (95% CI 4.10 to 12.00), mFPS=8.50 months (95% CI 4.00 to 11.40).

Mesothelin-positive patients with selected adenocarcinomas (NSCLC, triple negative breast, gastric including gastroesophageal junction) and thymic carcinoma will receive anetumab ravtansine as monotherapy at 6.50 mg/kg IV on a 21-day cycle. Patients with cholangiocarcinoma will receive anetumab ravtansine in combination with cisplatin (25 mg/m² IV day 1 and 8 on a 21-day cycle for up to 6 cycles) and patients with pancreatic adenocarcinoma will receive anetumab ravtansine in combination with gemcitabine (1000 mg/m² IV day 1 and 8 on a 21-day cycle).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Mice were subcutaneously inoculated with 5x10⁶ MSLN positive T1889 cells mixed with Matrigel. Treatment then began, and the experiments ran for a total of 4 weeks. The first treatment cohort of 32 mice consisted of vehicle control, isotype ADC control, and 15 mg/kg ARav, dosed at Q7D via intraperitoneal injection. A second treatment cohort of 30 mice occurred with groups consisting of vehicle control (Q14D), 7.5 mg/kg ARav (Q14D) monotherapy, 7.5 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy. A third treatment cohort of 32 mice occurred with groups consisting of vehicle control (Q14D), 3.75 mg/kg ARav (Q14D) monotherapy, 3.75 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Mice were subcutaneously inoculated with 5x10⁶ MSLN positive T1889 cells mixed with Matrigel. Treatment then began, and the experiments ran for a total of 4 weeks. The first treatment cohort of 32 mice consisted of vehicle control, isotype ADC control, and 15 mg/kg ARav, dosed at Q7D via intraperitoneal injection. A second treatment cohort of 30 mice occurred with groups consisting of vehicle control (Q14D), 7.5 mg/kg ARav (Q14D) monotherapy, 7.5 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy. A third treatment cohort of 32 mice occurred with groups consisting of vehicle control (Q14D), 3.75 mg/kg ARav (Q14D) monotherapy, 3.75 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Mice were subcutaneously inoculated with 5x10⁶ MSLN positive T1889 cells mixed with Matrigel. Treatment then began, and the experiments ran for a total of 4 weeks. The first treatment cohort of 32 mice consisted of vehicle control, isotype ADC control, and 15 mg/kg ARav, dosed at Q7D via intraperitoneal injection. A second treatment cohort of 30 mice occurred with groups consisting of vehicle control (Q14D), 7.5 mg/kg ARav (Q14D) monotherapy, 7.5 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy. A third treatment cohort of 32 mice occurred with groups consisting of vehicle control (Q14D), 3.75 mg/kg ARav (Q14D) monotherapy, 3.75 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy.

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g,7-10 weeks) from Taconic M&B were implanted on day 0 with either 3 x10⁶ MIA PaCa-2/vector,3 x10⁶ MIA PaCa-2/meso,1 x10⁶ HT-29/vector,1 x10⁶ HT-29/meso,3 x10⁶ OVCAR-3,or 3 x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. 0.03 mg/kg , 0.05 mg/kg , 0.2 mg/kg Anetumab ravtansine was i.v. to the tumor-bearing mice.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Mice were subcutaneously inoculated with 5x10⁶ MSLN positive T1889 cells mixed with Matrigel. Treatment then began, and the experiments ran for a total of 4 weeks. The first treatment cohort of 32 mice consisted of vehicle control, isotype ADC control, and 15 mg/kg ARav, dosed at Q7D via intraperitoneal injection. A second treatment cohort of 30 mice occurred with groups consisting of vehicle control (Q14D), 7.5 mg/kg ARav (Q14D) monotherapy, 7.5 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy. A third treatment cohort of 32 mice occurred with groups consisting of vehicle control (Q14D), 3.75 mg/kg ARav (Q14D) monotherapy, 3.75 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g, 7-10 weeks) from Taconic M&B were implanted on day 0 with either 3x10⁶ MIA PaCa-2/vector,3x10⁶ MIA PaCa-2/meso, 1x10⁶ HT-29/vector, 1x10⁶ HT-29/meso ,3x10⁶ OVCAR-3, or 3x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. 0.01 mg/kg , 0.05 mg/kg , 0.2 mg/kg Anetumab ravtansine was i.v. to the tumor-bearing mice.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Mice were subcutaneously inoculated with 5x10⁶ MSLN positive T1889 cells mixed with Matrigel. Treatment then began, and the experiments ran for a total of 4 weeks. The first treatment cohort of 32 mice consisted of vehicle control, isotype ADC control, and 15 mg/kg ARav, dosed at Q7D via intraperitoneal injection. A second treatment cohort of 30 mice occurred with groups consisting of vehicle control (Q14D), 7.5 mg/kg ARav (Q14D) monotherapy, 7.5 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy. A third treatment cohort of 32 mice occurred with groups consisting of vehicle control (Q14D), 3.75 mg/kg ARav (Q14D) monotherapy, 3.75 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Mice were subcutaneously inoculated with 5x10⁶ MSLN positive T1889 cells mixed with Matrigel. Treatment then began, and the experiments ran for a total of 4 weeks. The first treatment cohort of 32 mice consisted of vehicle control, isotype ADC control, and 15 mg/kg ARav, dosed at Q7D via intraperitoneal injection. A second treatment cohort of 30 mice occurred with groups consisting of vehicle control (Q14D), 7.5 mg/kg ARav (Q14D) monotherapy, 7.5 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy. A third treatment cohort of 32 mice occurred with groups consisting of vehicle control (Q14D), 3.75 mg/kg ARav (Q14D) monotherapy, 3.75 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Mice were subcutaneously inoculated with 5x10⁶ MSLN positive T1889 cells mixed with Matrigel. Treatment then began, and the experiments ran for a total of 4 weeks. The first treatment cohort of 32 mice consisted of vehicle control, isotype ADC control, and 15 mg/kg ARav, dosed at Q7D via intraperitoneal injection. A second treatment cohort of 30 mice occurred with groups consisting of vehicle control (Q14D), 7.5 mg/kg ARav (Q14D) monotherapy, 7.5 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy. A third treatment cohort of 32 mice occurred with groups consisting of vehicle control (Q14D), 3.75 mg/kg ARav (Q14D) monotherapy, 3.75 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g,7-10 weeks) from Taconic M&B were implanted on day 0 with either 3 x10⁶ MIA PaCa-2/vector,3 x10⁶ MIA PaCa-2/meso,1 x10⁶ HT-29/vector,1 x10⁶ HT-29/meso,3 x10⁶ OVCAR-3,or 3 x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. 0.05 mg/kg , 0.2 mg/kg Anetumab ravtansine was i.v. to the tumor-bearing mice.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g,7-10 weeks) from Taconic M&B were implanted on day 0 with either 3 x10⁶ MIA PaCa-2/vector,3 x10⁶ MIA PaCa-2/meso,1 x10⁶ HT-29/vector,1 x10⁶ HT-29/meso,3 x10⁶ OVCAR-3,or 3 x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. 0.03 mg/kg , 0.05 mg/kg , 0.2 mg/kg Anetumab ravtansine was i.v. to the tumor-bearing mice.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g,7-10 weeks) from Taconic M&B were implanted on day 0 with either 3x10⁶ MIA PaCa-2/vector, 3x10⁶ MIA PaCa-2/meso,1x10⁶ HT-29/vector, 1x10⁶ HT-29/meso, 3x10⁶ OVCAR-3, or 3x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. BAY 94-9343 administered at 0.05 mg/kg, 0.2 mg/kg (corresponding to 14.3 mg/kg ADC; Q3Dx3).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Mice were subcutaneously inoculated with 5x10⁶ MSLN positive T1889 cells mixed with Matrigel. Treatment then began, and the experiments ran for a total of 4 weeks. The first treatment cohort of 32 mice consisted of vehicle control, isotype ADC control, and 15 mg/kg ARav, dosed at Q7D via intraperitoneal injection. A second treatment cohort of 30 mice occurred with groups consisting of vehicle control (Q14D), 7.5 mg/kg ARav (Q14D) monotherapy, 7.5 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy. A third treatment cohort of 32 mice occurred with groups consisting of vehicle control (Q14D), 3.75 mg/kg ARav (Q14D) monotherapy, 3.75 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g,7-10 weeks) from Taconic M&B were implanted on day 0 with either 3x10⁶ MIA PaCa-2/vector, 3x10⁶ MIA PaCa-2/meso,1x10⁶ HT-29/vector, 1x10⁶ HT-29/meso, 3x10⁶ OVCAR-3, or 3x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. BAY 94-9343 administered at 0.05 mg/kg, 0.2 mg/kg (corresponding to 14.3 mg/kg ADC; Q3Dx3).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g,7-10 weeks) from Taconic M&B were implanted on day 0 with either 3 x10⁶ MIA PaCa-2/vector,3 x10⁶ MIA PaCa-2/meso,1 x10⁶ HT-29/vector,1 x10⁶ HT-29/meso,3 x10⁶ OVCAR-3,or 3 x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. 0.05 mg/kg , 0.2 mg/kg Anetumab ravtansine was i.v. to the tumor-bearing mice.

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g,7-10 weeks) from Taconic M&B were implanted on day 0 with either 3 x10⁶ MIA PaCa-2/vector,3 x10⁶ MIA PaCa-2/meso,1 x10⁶ HT-29/vector,1 x10⁶ HT-29/meso,3 x10⁶ OVCAR-3,or 3 x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. 0.03 mg/kg , 0.05 mg/kg , 0.2 mg/kg Anetumab ravtansine was i.v. to the tumor-bearing mice.

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g,7-10 weeks) from Taconic M&B were implanted on day 0 with either 3 x10⁶ MIA PaCa-2/vector,3 x10⁶ MIA PaCa-2/meso,1 x10⁶ HT-29/vector,1 x10⁶ HT-29/meso,3 x10⁶ OVCAR-3,or 3 x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. 0.01 mg/kg , 0.05 mg/kg , 0.2 mg/kg Anetumab ravtansine was i.v. to the tumor-bearing mice.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Mice were subcutaneously inoculated with 5x10⁶ MSLN positive T1889 cells mixed with Matrigel. Treatment then began, and the experiments ran for a total of 4 weeks. The first treatment cohort of 32 mice consisted of vehicle control, isotype ADC control, and 15 mg/kg ARav, dosed at Q7D via intraperitoneal injection. A second treatment cohort of 30 mice occurred with groups consisting of vehicle control (Q14D), 7.5 mg/kg ARav (Q14D) monotherapy, 7.5 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy. A third treatment cohort of 32 mice occurred with groups consisting of vehicle control (Q14D), 3.75 mg/kg ARav (Q14D) monotherapy, 3.75 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g, 7-10 weeks) from Taconic M&B were implanted on day 0 with either 3 x10⁶ MIA PaCa-2/vector,3 x10⁶ MIA PaCa-2/meso,1 x10⁶ HT-29/vector,1 x10⁶ HT-29/meso,3 x10⁶ OVCAR-3,or 3 x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. 0.01 mg/kg , 0.05 mg/kg , 0.2 mg/kg Anetumab ravtansine was i.v. to the tumor-bearing mice.

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g, 7-10 weeks) from Taconic M&B were implanted on day 0 with either 3 x10⁶ MIA PaCa-2/vector,3 x10⁶ MIA PaCa-2/meso,1 x10⁶ HT-29/vector,1 x10⁶ HT-29/meso,3 x10⁶ OVCAR-3,or 3 x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. 0.01 mg/kg , 0.05 mg/kg , 0.2 mg/kg Anetumab ravtansine was i.v. to the tumor-bearing mice.

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g, 7-10 weeks) from Taconic M&B were implanted on day 0 with either 3 x10⁶ MIA PaCa-2/vector,3 x10⁶ MIA PaCa-2/meso,1 x10⁶ HT-29/vector,1 x10⁶ HT-29/meso,3 x10⁶ OVCAR-3,or 3 x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. 0.01 mg/kg , 0.05 mg/kg , 0.2 mg/kg Anetumab ravtansine was i.v. to the tumor-bearing mice.

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g, 7-10 weeks) from Taconic M&B were implanted on day 0 with either 3 x10⁶ MIA PaCa-2/vector,3 x10⁶ MIA PaCa-2/meso,1 x10⁶ HT-29/vector,1 x10⁶ HT-29/meso,3 x10⁶ OVCAR-3,or 3 x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. BAY 94-9343 administered at 0.05 mg/kg,0.2 mg/kg (corresponding to 14.3 mg/kg ADC; Q3Dx3).

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g, 7-10 weeks) from Taconic M&B were implanted on day 0 with either 3 x10⁶ MIA PaCa-2/vector,3 x10⁶ MIA PaCa-2/meso,1 x10⁶ HT-29/vector,1 x10⁶ HT-29/meso,3 x10⁶ OVCAR-3,or 3 x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. BAY 94-9343 administered at 0.05 mg/kg,0.2 mg/kg (corresponding to 14.3 mg/kg ADC; Q3Dx3).

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g, 7-10 weeks) from Taconic M&B were implanted on day 0 with either 3 x10⁶ MIA PaCa-2/vector,3 x10⁶ MIA PaCa-2/meso,1 x10⁶ HT-29/vector,1 x10⁶ HT-29/meso,3 x10⁶ OVCAR-3,or 3 x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. BAY 94-9343 administered at 0.05 mg/kg,0.2 mg/kg (corresponding to 14.3 mg/kg ADC; Q3Dx3).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Four groups of mice,each consisting of 58 animals was set up and vital Hela cells were inoculated in a dose of 110e5 cells in 100 l by subcutaneous injection in the left inner flank on day 0. Animals in the treatment groups received 2 mg/kg,5 mg/kg,and 10 mg/kg anetumab ravtansine in 200 l injection buffer twice weekly by i.p. injection. Animals in the control group received injection buffer only.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Mice were subcutaneously inoculated with 5x10⁶ MSLN positive T1889 cells mixed with Matrigel. Treatment then began, and the experiments ran for a total of 4 weeks. The first treatment cohort of 32 mice consisted of vehicle control, isotype ADC control, and 15 mg/kg ARav, dosed at Q7D via intraperitoneal injection. A second treatment cohort of 30 mice occurred with groups consisting of vehicle control (Q14D), 7.5 mg/kg ARav (Q14D) monotherapy, 7.5 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy. A third treatment cohort of 32 mice occurred with groups consisting of vehicle control (Q14D), 3.75 mg/kg ARav (Q14D) monotherapy, 3.75 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Mice were subcutaneously inoculated with 5x10⁶ MSLN positive T1889 cells mixed with Matrigel. Treatment then began, and the experiments ran for a total of 4 weeks. The first treatment cohort of 32 mice consisted of vehicle control, isotype ADC control, and 15 mg/kg ARav, dosed at Q7D via intraperitoneal injection. A second treatment cohort of 30 mice occurred with groups consisting of vehicle control (Q14D), 7.5 mg/kg ARav (Q14D) monotherapy, 7.5 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy. A third treatment cohort of 32 mice occurred with groups consisting of vehicle control (Q14D), 3.75 mg/kg ARav (Q14D) monotherapy, 3.75 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Four groups of mice,each consisting of 58 animals was set up and vital Hela cells were inoculated in a dose of 110e5 cells in 100 l by subcutaneous injection in the left inner flank on day 0. Animals in the treatment groups received 2 mg/kg,5 mg/kg,and 10 mg/kg anetumab ravtansine in 200 l injection buffer twice weekly by i.p. injection. Animals in the control group received injection buffer only.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Mice were subcutaneously inoculated with 5x10⁶ MSLN positive T1889 cells mixed with Matrigel. Treatment then began, and the experiments ran for a total of 4 weeks. The first treatment cohort of 32 mice consisted of vehicle control, isotype ADC control, and 15 mg/kg ARav, dosed at Q7D via intraperitoneal injection. A second treatment cohort of 30 mice occurred with groups consisting of vehicle control (Q14D), 7.5 mg/kg ARav (Q14D) monotherapy, 7.5 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy. A third treatment cohort of 32 mice occurred with groups consisting of vehicle control (Q14D), 3.75 mg/kg ARav (Q14D) monotherapy, 3.75 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Four groups of mice,each consisting of 58 animals was set up and vital Hela cells were inoculated in a dose of 110e5 cells in 100 l by subcutaneous injection in the left inner flank on day 0. Animals in the treatment groups received 2 mg/kg,5 mg/kg,and 10 mg/kg anetumab ravtansine in 200 l injection buffer twice weekly by i.p. injection. Animals in the control group received injection buffer only.