Immune- and Non-Immune-Mediated Adverse Effects of Monoclonal Antibody Therapy: A Survey of 110 Approved Antibodies

Abstract

Identification of new disease-associated biomarkers; specific targeting of such markers by monoclonal antibodies (mAbs); and application of advances in recombinant technology, including the production of humanized and fully human antibodies, has enabled many improved treatment outcomes and successful new biological treatments of some diseases previously neglected or with poor prognoses. Of the 110 mAbs preparations currently approved by the FDA and/or EMA, 46 (including 13 antibody–drug conjugates) recognizing 29 different targets are indicated for the treatment of cancers, and 66, recognizing 48 different targets, are indicated for non-cancer disorders. Despite their specific targeting with the expected accompanying reduced collateral damage for normal healthy non-involved cells, mAbs, may cause types I (anaphylaxis, urticaria), II (e.g., hemolytic anemia, possibly early-onset neutropenia), III (serum sickness, pneumonitis), and IV (Stevens–Johnson syndrome, toxic epidermal necrolysis) hypersensitivities as well as other cutaneous, pulmonary, cardiac, and liver adverse events. MAbs can provoke severe infusion reactions that resemble anaphylaxis and induce a number of systemic, potentially life-threatening syndromes with low frequency. A common feature of most of these syndromes is the release of a cascade of cytokines associated with inflammatory and immunological processes. Epidermal growth factor receptor-targeted antibodies may provoke papulopustular and mucocutaneous eruptions that are not immune-mediated.

Improved Therapy of B-Cell Non-Hodgkin Lymphoma by Obinutuzumab-Dianthin Conjugates in Combination with the Endosomal Escape Enhancer SO1861

“…Nevertheless, no ADCs or immunotoxins have been approved by the competent authorities in the last century (denileukin diftitox was approved in 1999, but was a cytokine conjugate and not an ADC), and only one ADC (gemtuzumab ozogamicin) was approved in the first decade of the current century. Progress in antibody design and production, and of site-specific conjugation techniques, led to the approval of 12 ADCs with small molecule drugs but only one immunotoxin (moxetumomab pasudotox) with a protein toxin as effector (truncated Pseudomonas exotoxin PE38) to date [ 60 ], indicating that endosomal escape is still a problem for the use of very efficient biological macromolecules.…”

“…The target antigen CD20 is highly expressed on Raji cells while absent on Jurkat control cells [ 64 ]. Currently, there are four approved anti-tumor antibodies against CD20 on the market, obinutuzumab, ibritumomab, ofatumumab, and rituximab, and one further antibody, ocrelizumab, is approved to treat multiple sclerosis [ 60 ]. Obinutuzumab exhibits enhanced binding to low affinity immunoglobulin gamma Fc region receptor III and can induce in vitro an ADCC activity that is 35 to 100 times greater than that of ofatumumab and rituximab [ 65 , 66 ].…”

“…Such success suggests that further emphasis should be placed on the use of obinutuzumab. On the other hand, treatments with obinutuzumab are also accompanied by adverse events including thrombocytopenia, infusion related reactions, cardiac events, and hepatotoxicity [ 21 , 60 ] and the efficacy also still has a large potential for improvement. ADCs and immunotoxins have the general potential to reach this goal with immunotoxins being even better when the problem of endolysosomal accumulation and degradation of the payload can be adequately addressed.…”

Nutritional Treatment of Patients with Colorectal Cancer

“…The most common side effects of anticancer treatment for colorectal cancer, which may persist even after the end of oncological treatment, are neuropathy caused by the use of oxaliplatin and gastrointestinal disorders, which occur as a result of pelvic radiotherapy and the use of chemotherapeutics ( Table 1 and Table 2 ). Although chemotherapeutics mainly reduce cell division in its different stages, ionizing rays cause overlapping damage to the epithelium, microstructure, intestinal nervous system and disorders of intestinal microbiota [ 20 , 21 , 22 , 23 ].…”

Bispecific Antibody-Based Immune-Cell Engagers and Their Emerging Therapeutic Targets in Cancer Immunotherapy

“…As of December 2021, 110 therapeutic antibodies, including monoclonal antibodies (mAbs), bispecific antibodies (bsAbs), and antibody–drug conjugates (ADCs), have been approved by the United States Food and Drug Administration (US FDA) and/or the European Medicines Agency (EMA). Among them, 46 antibodies are indicated for cancer treatment [ 6 ]. Generally, immunoglobulin (Ig) G-based mAb—the most widely used mAb form for antibody therapy—comprises two heavy and two light chains.…”