Presented at AACR Annual Meeting 2022
Noemie Luong1, Nathalie Bellocq2, Léo Marx2, Mathilde Pantin2, Benjamin Tschumi1, Marie-Claude Roubaudi-Fraschini1, Camille Riff1, Manfred Mutter2, Antoine Attinger1
1Debiopharm International SA, Lausanne, Switzerland
2Debiopharm Research & Manufacturing SA, Martigny, Switzerland
We developed a novel drug linker technology, Multilink™, that enables the generation of stable and potent antibody drug conjugates (ADCs). It is selectively recognized and cleaved by the carboxydipeptidase activity of Cathepsin B, shown to be overexpressed in cancer cells. The technology allows a fast and specific cleavage, which results in efficient drug release in the tumor. Different payloads can be attached to antibodies, and the drug to antibody ratio (DAR) can be modulated up to DAR16, resulting in customized cytotoxic activity. Here we present the characteristics of MultilinkTM using Trastuzumab as the targeting antibody (targeting Human epidermal growth factor receptor 2 (Her2)), testing different payloads and different DARs.
Trastuzumab based MultilinkTM ADCs (T-Multilink™ ADCs) were generated and first tested in vitro. Kinetic release experiments show that the payload could be cleaved and released within minutes (Figure 1). In cellular assays, ADCs were tested for their activity and proved highly potent, especially in the Jimt-1 Her2 low expressing cells. Increasing the DAR from 8 to 16 correlates with improved activity (Figure 2), while the aggregation levels remained low (Figure 3).
We then tested the molecules in a breast cancer model expressing low levels of Her2. A Trastuzumab Multilink™ ADC with mertansine (DM1) at DAR8 showed superior activity, including complete tumor regressions, as compared to T-DM1 and T-DXd. In the same model, a MultilinkTM ADC with Auristatin F (AF) was even more active and able to induce durable complete regression in all mice (Figure 6). Both compounds were well tolerated. In addition, the Trastuzumab MultilinkTM ADCs showed total antibody PK profiles comparable to T-DM1 and T-DXd (Figure 5). Plasma stability was also assessed in vitro for T-Multilink™ DM1 ADC and stability was good after incubation in human and murine serum (Figure 4).
In conclusion, we are able to produce stable and high DAR ADCs with improved efficacy using the Multilink™ technology.