Desenvolvimento de Conjugados de Anticorpos-Degradadores Altamente Específicos e Potentes para o Tratamento do Cancro da Mama Triplo Negativo: Um passo em frente na Terapia de Precisão do Cancro

The proposed project addresses critical challenges in breast cancer therapy, focusing on the TNBC, a subtype that is notoriously resistant to conventional therapies and poses a significant global health burden. TNBC is not only a significant threat to human health, but also affects mammalian counterparts such as cats. Thus, there is an urgent need to develop targeted, effective, and safe treatments for TNBC that can benefit both human and feline patients, emphasizing the significance and broad impact of the proposed research. The ambition of this project extends beyond conventional disciplinary boundaries by integrating concepts from comparative oncology, aimed at developing a novel class of therapeutics based on PROTACs, as they offer a unique mechanism of action by inducing targeted protein degradation. However, they present some drawbacks such as off-target effects and limitations in tissue penetration, PK, and bioavailability. To overcome these challenges, our project will explore the development of a novel concept emerging in cancer therapy, named Degrader-Antibody Conjugates (DACs), which involves fusing antibodies with PROTACs to enable precise delivery into cancer cells. This innovative approach aims to enhance the targeting and therapeutic properties of PROTACs, thus bypassing the current limitations in cancer therapeutics. For that, our project aims to increase the tumor targeting of DACs by developing a highly specific antibody against Trop-2, a promising receptor validated for TNBC targeting. To achieve this goal, we will explore our sdAb platform, which offers advantages such as improved tumor penetration, selective payload conjugation, and lower manufacturing costs. Furthermore, the project aims to select a PROTAC that targets proteins primarily expressed in TNBC cells and involved in tumorigenesis, thereby minimizing off-target effects and maximizing therapeutic efficacy. The selection of this PROTAC will involve a PROTAC library and a high-throughput screening approach, employing both feline and human TNBC cells. The selected PROTAC will be conjugated with the anti-Trop-2 sdAb, leading to the generation of a highly specific and potent new class of DACs with dual targeting properties (sdAb targets Trop-2 and PROTOAC targets the intracellular protein). It is our aim to patent this engineered therapeutic DAC to apply for further funding opportunities, facilitating the progression into scale-up process development and proceeding in the future into preclinical and clinical studies in cats, and then translate it into the human setting. Our institution (FMV) is in an excellent position to proceed with this step since our faculty houses a Teaching Veterinary Hospital with an Oncology Center, where we have access to a significant and well-characterized population of cats with TNBC. This provides us with access to TNBC primary cells to validate our DAC molecule and sets the stage for future clinical studies. With this strategy and comparative oncology approach, we will push the boundaries of cancer research and pave the way for a step forward in precision cancer therapy for TNBC. Overall, the proposed objectives demonstrate a high level of innovation and ambition to significantly advance the field of cancer therapy by addressing the unmet clinical needs of TNBC patients across species, thereby contributing to the United Nations Sustainable Development Goals, particularly Goal 3: Good Health and Well-Being.