Abstract 4115: ADCs optimization lead to a significant anti-tumoral activity in lymphoma and breast tumor xenograft mouse models
Authors: Mirjolet Jean-Francois , Bertaux Audrey , Benhamouche-Trouillet Samira , Grondin Pascal , Sahal Ambrine , Serin Guillaume , Juen Ludovic , Baltus Christine , Gély Camille , Feuillâtre Ofelia , Desgranges Audrey , Viaud-Massuard Marie-Claude , Martin Camille 
Published: September 2020

Introduction: The Antibody-Drug Conjugates (ADCs)-based therapy has revealed a field of perspectives by increasing the specificity and the efficacy of the anti-tumoral drug treatment. McSAF is a company focused in bio-organic and bioconjugates chemistry and has developed a new linker technology solution, allowing to improve ADCs homogeneity and stability resulting in a higher anti-tumoral effect on a HER2-positive breast tumor model (BT-474 cell line) and a CD30-positive non-Hodgkin's lymphoma model (Karpas-299 cell line).

Methods: The anti-tumoral activity of McSAF-ADCs was tested both in vitro and in vivo. In both cell line models, an MTS-based cell viability assay has been performed in presence of the standard of care (SOC, Kadcyla® (T-DM1) = Trastuzumab emtansine, or Adcetris® = Brentuximab vedotin) or the equivalent McSAF-ADCs at different concentrations for 72 to 96 hours. In vivo studies were conducted with xenograft models of HER2-positive tumors in Balb-c nude mice and CD30-positive lymphoma in CB17 SCID mice. After tumor induction, animals bearing well-established tumors (≈100-200 mm3) were randomized and treated once or twice with vehicle, SOC or McSAF-ADCs at one or two doses. During the study course, the animals were monitored for several weeks for their behavior, body weight and tumor volume.

Results: In the HER2-positive breast tumor model, in vitro experiments revealed a higher cytotoxicity of MF-TTZ-MMAE (IC50 = 1 nM) on BT-474 cell line compared to the SOC (IC50 ≈ 100 nM). In vivo, the treatment with MF-TTZ-MMAE was well tolerated at all tested doses (1 and 5 mg/kg). At 5 mg/kg, the MF-TTZ-MMAE compound induced a full regression of tumors after second treatment. At the end of the study, all animals treated with MF-TTZ-MMAE were still tumor free, seven weeks after end of treatment, which was not observed on animals treated with T-DM1 (only 25% tumor-free animals).

In the CD30-positive non-Hodgkin's lymphoma model, the MTS assay revealed similar efficacy for brentuximab vedotin and MF-BTX-MMAE (IC50 ≈ 0.1 nM) on Karpas-299 cell line. In vivo, the treatment with MF-BTX-MMAE was well tolerated at all tested doses (0.5 and 1 mg/kg). The single treatment with MF-BTX-MMAE had a marked, dose dependent, anti-tumoral efficacy with 40% and 100% of animals showing complete regression at the end of the study (9 weeks after treatment) for doses of 0.5 mg/kg and 1 mg/kg respectively. And again, the treatment with MF-BTX-MMAE at 0.5 mg/kg resulted in a higher tumor growth inhibition and better survival than with the clinical equivalent ADC Adcetris® at the equivalent dose.

Conclusion: Altogether, these promising results reveal that improvement of ADCs stability and homogeneity leads to a higher anti-tumoral activity as tested both in vitro and in vivo HER2-positive and CD30-positive tumor models.

Citation Format: Jean-Francois Mirjolet, Audrey Bertaux, Samira Benhamouche-Trouillet, Pascal Grondin, Ambrine Sahal, Guillaume Serin, Ludovic Juen, Christine Baltus, Camille Gély, Ofelia Feuillâtre, Audrey Desgranges, Marie-Claude Viaud-Massuard, Camille Martin. ADCs optimization lead to a significant anti-tumoral activity in lymphoma and breast tumor xenograft mouse models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4115.