Antibody-drug conjugates in breast cancer: overcoming resistance and boosting immune response

Abstract

Antibody-drug conjugates (ADCs) have emerged as a revolutionary therapeutic class, combining the precise targeting ability of monoclonal antibodies with the potent cytotoxic effects of chemotherapeutics. Notably, ADCs have rapidly advanced in the field of breast cancer treatment. This innovative approach holds promise for strengthening the immune system through antibody-mediated cellular toxicity, tumor-specific immunity, and adaptive immune responses. However, the development of upfront and acquired resistance poses substantial challenges in maximizing the effectiveness of these therapeutics, necessitating a deeper understanding of the underlying mechanisms. These mechanisms of resistance include antigen loss, derangements in ADC internalization and recycling, drug clearance, and alterations in signaling pathways and the payload target. To overcome resistance, ongoing research and development efforts are focused on urgently identifying biomarkers, integrating immune therapy approaches, and designing novel cytotoxic payloads. This Review provides an overview of the mechanisms and clinical effectiveness of ADCs, and explores their unique immune-boosting function, while also highlighting the complex resistance mechanisms and safety challenges that must be addressed. A continued focus on how ADCs impact the tumor microenvironment will help to identify new payloads that can improve patient outcomes.

Figure 1. Mechanisms of resistance.

Resistance mechanisms to antibody-drug conjugates (ADCs) can be broadly classified into two categories: antibody resistance and payload resistance. Antibody resistance mechanisms include clearance of ADC, antigen loss, and derangement in internalization. Payload resistance mechanisms include alterations in the payload target, upregulation of antiapoptotic proteins, activation of cell signaling pathways, and clearance of the payload.

Figure 2. Antibody-drug conjugates in the cancer-immunity cycle.

ADCs play a crucial role in activating tumor immunity across all stages of the cancer-immunity cycle. Targeted release of the ADC payload leads to tumor cell death and subsequent release of DAMPs that stimulate activation of dendritic cells. Mature dendritic cells facilitate antigen uptake and migration to lymph nodes. In the lymph nodes, ADCs reduce Tregs and augment MHC-I expression, thereby promoting the effective activity of cytotoxic (effector) T cells. ADCs enhance leukocyte infiltration and expand CD4⁺ and CD8⁺ T cells, NK cells, and IFN-γ production. Secretion of proinflammatory chemoattractants such as IFN-γ recruits immune cells including NK cells, dendritic cells, and CD4⁺ and CD8⁺ T cells. The antibody component of ADCs activates the immune system via antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC).

Figure 3. Payloads under investigation.

The modular design of ADCs allows for payloads to be used interchangeably. Broad categories of payloads under investigation include proteolysis-targeting chimeras, immune stimulators, transcription inhibition, and genetic materials.