New antibodies - clinical context, efficacy and safety

摘要

Improvements in techniques of monoclonal antibodies synthesis have enabled new therapeutic applications in oncology, including the use of conjugated antibodies and bispecific antibodies. Antibody-drug conjugates (ADCs) are consist in targeting a tumour antigen with an antibody combined via a linker with a cytotoxic agent too potent to be administered directly. The respective properties of the antigen target, the antibody used, the linker and the payload, particularly in terms of the number of cytotoxic molecules per antibody, are fundamental to the therapeutic index of ADCs, which has been considerably improved by technological progress. Their pharmacokinetic properties are complex and their mechanisms of action are unclear, involving not only internalization of the antibody conjugate after binding to its antigen target but also mechanisms of antibody-dependent cytotoxicity and diffusion of the toxin to adjacent cells (bystander effect). Their tolerance profile is mainly payload-dependent but sometimes dependent on target-independent ADC uptake or off-tumour on-target binding. Among the antibody conjugates in development, trastuzumab-deruxtecan targeting oncogenic HER2 mutations has shown a higher level of activity than the older-generation T-DM1, illustrating the impact of technological progress, and this will be a major therapeutic weapon. Patritumab-deruxtecan targeting HER3 is showing good results in patients with EGFR mutation-dependent adenocarcinoma, in cases of acquired resistance to EGFR inhibitors, regardless of the mechanism of resistance. Other antibodies targeting TR0P2 or MET antigens have demonstrated activity in patients with refractory disease with response rates of around 20%. The development of conjugated antibodies, that improve the therapeutic index of cytotoxic drugs and distinguish between tumour cells and healthy cells, is rapidly increasing and their role is becoming more evident.