ADC MI130004 , Otro avance que será presentado por la Compañía es el desarrollo del anticuerpo conjugado, MI130004, que combina el anticuerpo monoclonal trastuzumab (que se une a la proteína de superficie HER-2) y el compuesto de origen marino PM050489 .Los resultados de este estudio demuestran que el tratamiento con MI130004 produce un marcado y duradero efecto antitumoral en modelos preclínicos de tumores de mama que sobreexpresan HER2. Los datos destacan el incremento de la supervivencia de los animales tratados y demuestran el potencial de este nuevo producto.
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Abstract Number: 2480
Presentation Title: MI130004, a new antibody-drug conjugate, induces strong, long-lasting antitumor effect in HER2 expressing breast tumor models .
Presentation Time:
Monday, Apr 20, 2015, 1:00 PM - 5:00 PM .
Author Block :
Pablo M. Aviles1, Maria Jose J. Guillen1, Alberto Gallardo2, Maria Virtudes Cespedes3, Ramon Mangues2, Heiner Fiebig4, Natalie Hartman4, Juan Manuel Dominguez1, Luis Francisco Garcia1, Carlos Galmarini1, Carmen Cuevas1. 1PharmaMar S.A., Madrid, Spain; 2Institut d`Investigacions Biomèdiques Sant Pau and CIBER-BBN, Barcelona, Spain; 3Institut d`Investigacions Biomèdiques Sant Pau and CIBER-BBN, Spain., Barcelona, Spain; 4Oncotest GmbH, Freiburg, Germany .
Abstract Body: Background:
Antibody-drug conjugates (ADC`s) have emerged as powerful tools for the treatment of cancer, combining the potency of cytotoxic molecules with the selectivity of antibodies targeted towards specific antigens. Marine compounds represent an interesting opportunity worth exploring as they possess the requirements needed to be considered promising payloads. The in vivo results obtained with a new ADC, MI130004, in HER2 expressing breast tumors are presented here.
Materials and Methods:
To evaluate the long lasting antitumor effect induced by MI130004, immunodefficient female mice were subcutaneously implanted with HER2 expressing breast lines namely, JIMT-1, BT-474 and MAXF574.Tumor (ca. 100 mm3) bearing
animals were randomly allocated (Day 0) to receive MI130004 (10mg/kg), trastuzumab (30 or 10 mg/kg) or placebo (N=8-10/group). Intravenous treatments were weekly administered for 5 consecutive weeks and then, tumor volume growth was recorded 2-3 times per week. For survival evaluation, time to endpoint was define as the time from Day 0 to death as a results of tumor growth (>2000 mm3) or any other cause (e.g., tumor necrosis). Statistical differences were assessed by Kaplan-Meier curves with the log rank test. The follow-up period was extended until 90 (MAXF574) or 120 days (JIMT-1 and BT-474) after the initiation day (Day 0). Then, surviving animals were sacrificed, tumor (or skin around the former tumor site) dissected free, formalin fixed and paraffin embedded for histopathology evaluations.
Results:
The treatment with MI130004 induced a long lasting antitumor effect with statistically significant increases in median survival time compared to either placebo ( P = 0.0336, P = 0.0001 and P < 0.0001 for BT-474, JIMT-1 and MAXF574, respectively ) or trastuzumab treatments ( P = 0.0005 and P < 0.0001 for JIMT-1 and MAXF574, respectively ). Seventy one percent of mice xenografted with JIMT-1 and treated with MI130004 survived up to Day 120. Out of them, 40% experienced a complete tumor remission ( tumor < 63 mm3 ). All animals originally xenografted with BT-474 experienced complete tumor remissions by Day 120. On Day 90, 90.0% of the population xenografted with MAXF574 survived and 55.6% of these experienced complete tumor remission.
Conclusions:
The treatment with MI130004 on mice bearing HER2 expressing breast tumors resulted in strong, long lasting antitumor activity, including complete tumor remissions. These results strongly suggest that MI130004 is a new ADC with extraordinary therapeutic anti-cancer properties. b>