Eligible patients: platinum-resistant/refractory high-grade ovarian/fallopian tube/primary peritoneal cancer (GCIC criteria; measurable disease required for Phase 2); ECOG ≤2; adequate hematologic/organ function; MSLN-positive (≥30% tumor cells with 2+ staining) for Phase 2 only. Key exclusions: recent chemotherapy/radiotherapy (≤4 weeks); strong CYP3A4 modulators; uncontrolled comorbidities (HTN, cardiovascular/CNS events, infections); pregnancy; prior bevacizumab/weekly paclitaxel in platinum-resistant setting. Brain metastases allowed if stable ≥4 weeks post-radiation without steroids.

Inclusion: Unresectable/metastatic pancreatic cancer (1-2 prior chemo lines; 2+/3+ mesothelin expression in ≥30% tumor cells), ECOG 0-1, adequate organ function. Exclusion: Prior mesothelin-targeted therapy, significant cardiac/ocular/CNS conditions, active infections (HIV/HBV/HCV), recent major surgery, unresolved toxicity >Grade 1, or pregnancy. Brain metastases allowed if stable >6 months post-therapy with negative imaging.

Inclusion: Metastatic/unresectable pancreatic adenocarcinoma (mesothelin-positive; ≥5% tumor cells for escalation, ≥30% 2+/3+ for expansion), ≥1 prior systemic therapy, ECOG 0-1, measurable disease, accessible lesions for biopsies, adequate organ function. Exclusion: Active CNS metastases/uncontrolled infections; recent major surgery/live vaccines; unresolved CTCAE ≥G2 toxicities (except alopecia/G2 neuropathy); autoimmune/inflammatory diseases (exceptions: stable hypothyroidism/vitiligo); strong CYP3A4 modulators; pregnancy/HIV-HBV-HCV (unless controlled); prior organ transplants. Corneal disorders may exclude per ophthalmologist assessment.

Inclusion: Japanese patients (&ge;20 years) with ECOG 0-1, life expectancy &ge;12 weeks, advanced solid tumors (refractory/no standard therapy), measurable disease (RECIST 1.1), and adequate organ function. Exclusion: Recent anticancer therapy (<2 weeks), significant cardiac disease (CHF NYHA III/IV, recent MI/unstable angina, QTc >470 ms, LVEF <50%, uncontrolled hypertension), active HIV/HBV/HCV, LQTS history, or clinically significant eye disorders.

The study will assess treatment-emergent adverse events (TEAEs) graded by NCI CTCAE v4.03 over 9 weeks. Pharmacokinetic parameters (Cmax, AUC, tmax) for BAY94-9343, its total antibody compound, DM4, and metabolite DM4-Me will be measured across cycles (1-6) at multiple timepoints, including dose-normalized values (Cmax/D, AUC/D) and body-weight-adjusted metrics (Cmax,norm, AUCnorm) to evaluate drug exposure.

Inclusion: Adults with unresectable, mesothelin-positive (&ge;10% tumor cells, 2+/3+ intensity) lung adenocarcinoma (stage IIIB/IV), prior platinum/immunotherapy, ECOG &le;2, measurable disease (RECIST), and adequate organ function. Exclusion: Concurrent cancers, uncontrolled CVD (NYHA III/IV CHF, recent MI/stroke, QTc >480 ms), active HBV/HCV/HIV, unresolved CTCAE >1 toxicity (except alopecia/anemia), recent major surgery/radiotherapy to target lesions, strong CYP3A4 modulators, or prior anetumab ravtansine exposure. Corneal disorders may disqualify per investigator assessment.

The Recommended Phase 2 Dose (RP2D) will be determined as the highest dose with ≤1 dose-limiting toxicity (DLT), defined as treatment-emergent adverse events (TEAEs) like prolonged grade 4 neutropenia during Cycle 1. Efficacy endpoints include the proportion of subjects achieving partial/complete response (≥30% reduction/disappearance of target lesions per RECIST), assessed at 6 weeks.

Key secondary outcomes include progression-free survival (time to progression/death; RECIST-defined as ≥20% lesion growth + ≥5mm absolute increase), duration of response (time from CR/PR to progression), and overall survival (time to death from any cause). Safety will be monitored via CTCAE v4.0-graded serious/non-serious adverse events during the safety run-in phase (2 months).

Inclusion: Advanced/metastatic NSCLC patients (Phase I: no standard therapy; Phase II: &ge;1 prior platinum regimen) with mesothelin expression (&ge;30% tumor cells, Ventana IHC 2+/3+), ECOG 0-1, measurable disease (Phase II), and adequate organ function. Exclusion: Prior anti-PD-1/PD-L1 therapy (except anti-CTLA-4 with specific criteria), CNS metastases (unless asymptomatic/stable), uncontrolled CVD (NYHA III/IV CHF, recent angina/MI), active infections, autoimmune diseases (exceptions for stable conditions), recent major surgery/radiotherapy, or corneal disorders. Pregnant women and those with untreated HBV/HCV or severe immunosuppression are excluded.

The Phase I portion aims to determine the Maximum Tolerated Dose (MTD) of anetumab ravtansine combined with atezolizumab, defined as the highest dose level where ≤1 out of 6 patients experience dose-limiting toxicities (DLTs) within 21 days. In Phase II, efficacy will be assessed via the confirmed response rate (CR/PR on two consecutive scans ≥4 weeks apart), analyzed using exact binomial 95% CIs.

Phase I will evaluate clinical activity (CR, PR, SD, PD via descriptive statistics) and adverse event incidence (CTCAE v4.0 graded) over 21 days post-treatment. Phase II endpoints include overall survival (time to death, Kaplan-Meier estimation up to 2 years), progression-free survival (time to progression/death; 1- and 2-year rates reported), and safety monitoring.

Inclusion: Malignant pleural mesothelioma patients (post-platinum therapy, mesothelin-positive [&ge;30% tumor cells], measurable disease per RECIST/mRECIST) with ECOG <2, adequate organ function, and contraception compliance. Exclusion: Active brain metastases, recent anti-PD-1/PD-L1 therapy, unresolved CTCAE >1 toxicity (except neuropathy/alopecia), CYP3A4 modulators, pregnancy, HIV/HBV/HCV (unless controlled), corneal epitheliopathy, or interstitial lung disease. Prior transfusions/G-CSF within 4 weeks or live vaccines within 30 days are prohibited.

The Phase II portion will evaluate confirmed tumor response rate (CR + PR per RECIST 1.1) over 2 years, comparing treatment arms via one-sided z-test (alpha=0.10). The Phase I component will determine the Recommended Phase 2 Dose (RP2D) of anetumab ravtansine combined with pembrolizumab, assessing toxicity in all treated patients (DLT evaluability excludes non-toxicity-related discontinuations).

Key Phase II endpoints include duration of response (Kaplan-Meier estimation from treatment start, log-rank test for arm comparison), overall survival (death from any cause, Kaplan-Meier/log-rank), and progression-free survival (time to progression/death per RECIST 1.1). Pharmacodynamic analyses will correlate megakaryocyte potentiating factor levels with response (Wilcoxon/Jonckheere-Terpstra tests) and explore mononuclear phagocyte system biomarkers (linear regression). Adverse events will be tracked via PRO-CTCAE over 2 years.

Key efficacy endpoints included OS (time to death; log-rank test), Objective Response Rate (ORR, CR+PR per mRECIST), Disease Control Rate (DCR, CR+PR+SD), Duration of Response (DOR), and Durable Response Rate (DRR, response ≥180 days). Symptom improvement (MDASI-MPM) and pain metrics (TTWP, improvement rates) were tracked. Treatment-emergent adverse events (TEAEs) and fatal outcomes were analyzed through Jul-2019.

Inclusion Criteria: Adults (&ge;18) with unresectable epithelial mesothelioma or nonsquamous NSCLC (chemotherapy-naive or pretreated, though NSCLC subjects must have received FDA-approved therapies first) and measurable disease (RECIST 1.1/mRECIST), ECOG 0-1, life expectancy &ge;12 weeks, and adequate organ function. Exclusion Criteria: Prior/distinct cancers (unless cured >3 years prior), bleeding disorders (CTCAE &ge;G2), active CNS metastases, uncontrolled cardiovascular disease (NYHA III/IV), hypertension (&ge;160/100 mmHg), biliary obstruction, organ transplantation, drug hypersensitivity, active HBV/HCV/HIV, serious infections (CTCAE &ge;G2), recent anticancer therapies/radiotherapy (within 4 weeks), or anticoagulation started within 2 weeks pre-treatment.

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).

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).

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).

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. 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).

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.

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.