Mechanisms of action and resistance to anti-HER2 antibody-drug conjugates in breast cancer.

Human epidermal growth factor 2 (HER2)-positive breast cancer (BC) represents nearly 20% of all breast tumors. Historically, these patients had a high rate of relapse and dismal prognosis. The advent of HER2-targeting monoclonal antibodies such as trastuzumab followed by pertuzumab had improved the prognosis of HER2-positive metastatic BC. More recently, antibody-drug conjugates (ADCs) are now reshaping the treatment paradigm of solid tumors, especially breast cancer. Tratsuzumab emtansine (T-DM1) was one of the first ADC developed in oncology and was approved for the management of HER2-positive metastatic BC. In a head-to-head comparison, trastuzumab deruxtecan (T-DXd) defeated T-DM1 as a second-line treatment. The efficacy of ADCs is counterbalanced by the appearance of acquired resistance to these agents. In this paper, we summarize the mechanisms of action and resistance of T-DM1 and T-DXd, as well as their clinical efficacy. Additionally, we also discuss potential strategies for addressing resistance to ADC.

The Evolving Role of Bispecific Antibodies in Diffuse Large B-Cell Lymphoma.

The advent of targeted therapies such as monoclonal antibodies, adoptive T-cell therapies, and antibody-drug conjugates (ADCs) dramatically changed the treatment landscape of diffuse large B-cell lymphoma (DLBCL) over the last two decades. Rituximab was the first one approved. Chimeric antigen receptor T-cells are currently approved as second-line treatment in patients with DLBCL refractory to first-line chemo-immunotherapy. Polatuzumab, a CD79b-targeting ADC, is approved as first-line treatment in high-risk patients in combination with chemo-immunotherapy. Bispecific antibodies (BsAbs) are a novel category of drugs that are also changing the treatment paradigm of patients with DLBCL. They are engineered to bind to two different targets at the same time. To date, two BsAbs (glofitamab and epcoritamab) are approved as monotherapy in third-line treatment in DLBCL. Combination strategies with chemotherapy, immunotherapy, and ADCs are currently under investigation with encouraging results in first-line or subsequent lines of treatment. In the following review, we focus on the structure of BsAbs, the mechanism of action, clinical efficacy, and the mechanisms of resistance to BsAbs.