performed an overall proofread. polatuzumab vedotin, mosenutuzumab, epcoritamab, glofitamab == 1. Introduction == In the last decade, immunotherapy experienced a very rapid development and established itself as one of the fundamental parts of cancer treatment. Its main aim is to activate and encourage the bodys own immune system to distinguish and destroy malignant cells [1]. In 1997, rituximab K+ Channel inhibitor was the very first CD20-specific mAb to obtain regulatory approval, and rapidly became a key part of chemotherapeutic regimens (so-called chemoimmunotherapy) in the care for both B-cell non-Hodgkin lymphoma (B-NHL) and chronic lymphocytic leukaemia (CLL) [2]. Since then, antibody drug-conjugates (ADCs), immune checkpoint inhibitors, and both bispecific and trispecific antibodies for CAR-T cell therapy have been developed. Each class of these immunotherapeutic modalities has a unique mechanism of action, structure, and pharmacokinetic properties which are reflected in their specific treatment-related toxicities. Mature B-cell neoplasms are a diverse group of lymphoid K+ Channel inhibitor disorders with varying clinical manifestations, pathologic features, and outcomes. Diffuse large B-cell lymphoma (DLBCL) along with follicular lymphoma (FL) represent the most common aggressive and indolent histological subgroups of B-NHL with the incidence of ~5.6/100.000/year and ~2.7/100.000/year respectively (https://seer.cancer.gov/statfacts/html/dlbcl.htmlaccessed on 19 October 2021). Together they comprise 50% of all B-NHL cases [3]. Chronic lymphocytic leukemia is another indolent B-cell malignancy with an incidence of ~4.9/100.000/year (https://seer.cancer.gov/statfacts/html/dlbcl.htmlaccessed on 19 October 2021), and accounts for 2530% of newly diagnosed leukemias in the Western world [4]. Expression of tumor cell antigens varies according to diagnosis and may change during the treatment. Nevertheless, some markers such as B-cell-associated antigens (CD19, CD20, CD22, and CD79b) are commonly expressed on mature B-lymphocytes including neoplastic ones, and became targets for different immunotherapeutic modalities [5]. Despite that, molecules more selectively expressed on malignant cells and ideal targets on effector cells (e.g., T-cells, NK cells, APCsantigen presenting cells, macrophages) are still being explored. Some of such antigens (CD30, CD47, CD37, CD70) will be described later in more detail. Our review is focused on the current role of ADCs and bsAbs in B-NHL and CLL treatment. We discuss mechanism of action specific for each class, point to differences in their serious treatment-related toxicities and give an overview of the most important preclinical and clinical trials.Figure 1shows examples of some immunotherapeutic agents used in B-NHLs. == Figure 1. == Examples of currently used and tested immunotherapeutic modalities in the treatment of B-cell non-Hodgkin lymphomas. mAb, monoclonal antibody; bsAb, bispecific antibody; TCE, T-cell engager; BiTE, bispecific T-cell engager; CAR-T cell, chimeric antigen receptor T cell; ADC, antibody-drug conjugate; BCR, B-cell receptor. == 2. Antibody-Drug Conjugates == Antibody-drug conjugates could be considered a bridge between conventional chemotherapy which eliminates all rapidly dividing cells and more targeted immunotherapy combining the best anti-tumor properties of each of them [6]. Antibody-drug conjugates consist of three main parts: the mAb, the cytotoxic payload, and the linker, which connects the two together. Monoclonal antibody serves as a transporter of the payload and binds to the specific antigen on the surface of tumor cells. The antigen then triggers the internalization of the whole complex via endocytosis, the linker is degraded by lysosomal enzymes and the payload is released. Upon release, the cytotoxic agent eliminates the tumor cell by various mechanisms, most often by DNA damage or interaction with microtubules [7,8]. Several ADCs (e.g., brentuximab vedotin) exert their anti-tumor toxicity also via bystander Rabbit Polyclonal to 4E-BP1 (phospho-Thr69) effect that is characterized as capability of the payload to permeate through cell membranes and kill neighboring cells, regardless of the presence of the target antigen [6]. Monoclonal antibody should be directed against antigen highly expressed on tumor cells and with limited or no expression on normal tissues to avoid excessive off target toxicity [7]. Payload is required to be highly toxic in subnanomolar concentrations, to be able to conjugate with the antibody, and to remain stable in physiological conditions [6,8]. Nevertheless, the essential components of K+ Channel inhibitor ADC from the perspective of biochemical stability are linkers and there are two types of them (cleavable and non-cleavable) [9]. The first group has the cleavage site located between payload and monoclonal antibody and the separation process may occur within the endosome, lysosome or cytosol itself, while the second group needs complete proteolytic degradation of mAb backbone within the lysosome to release the payload [7,8,9]. Another important attribute of ADC in terms of effectiveness and security is definitely.