monomethyl-auristatin-e and Inflammation

Breast tumors generally consist of a diverse population of cells with varying gene expression profiles. Breast tumor heterogeneity is a major factor contributing to drug resistance, recurrence, and metastasis after chemotherapy. Antibody-drug conjugates (ADCs) are emerging chemotherapeutic agents with striking clinical success, including T-DM1 for HER2-positive breast cancer. However, these ADCs often suffer from issues associated with intratumor heterogeneity. Here, we show that homogeneous ADCs containing two distinct payloads are a promising drug class for addressing this clinical challenge. Our conjugates show HER2-specific cell killing potency, desirable pharmacokinetic profiles, minimal inflammatory response, and marginal toxicity at therapeutic doses. Notably, a dual-drug ADC exerts greater treatment effect and survival benefit than does co-administration of two single-drug variants in xenograft mouse models representing intratumor HER2 heterogeneity and elevated drug resistance. Our findings highlight the therapeutic potential of the dual-drug ADC format for treating refractory breast cancer and perhaps other cancers.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Line, Tumor; Female; Humans; Immunoconjugates; Immunohistochemistry; Inflammation; Mice; Oligopeptides; Receptor, ErbB-2; Trastuzumab; Xenograft Model Antitumor Assays

Bioorthogonal chemistry capable of operating in live animals is needed to investigate biological processes such as cell death and immunity. Recent studies have identified a gasdermin family of pore-forming proteins that executes inflammasome-dependent and -independent pyroptosis

Topics: Animals; Coumarins; Delayed-Action Preparations; Female; Green Fluorescent Proteins; HeLa Cells; Humans; Immunoconjugates; Inflammasomes; Inflammation; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Oligopeptides; Programmed Cell Death 1 Receptor; Proteins; Pyroptosis; Silanes; T-Lymphocytes; Trastuzumab; Xenograft Model Antitumor Assays