itolizumab

Itolizumab targets the CD6-ALCAM axis to limit T-cell responses and brain barrier diapedesis in multiple sclerosis.

González-Muñoz Cynthia C, Baeten Paulien P, Hermans Doryssa D, Hoeks Cindy C et al.

Genetic and preclinical data highlight CD6 as a promising target for multiple sclerosis (MS), yet the impact of clinically available CD6-targeting treatments on MS immunopathogenesis remains insufficiently defined. Itolizumab, a humanized anti-CD6 antibody with established safety and clinical efficacy in other autoimmune disorders, represents a potential candidate to interrogate this pathway in MS. CD6 expression was quantified by flow cytometry on circulating lymphocytes from MS patients and healthy donors. Functional consequences of CD6 blockade using itolizumab were evaluated using human in vitro models of brain barriers, including T cell diapedesis, barrier integrity, and inflammatory responses. T cell co-cultures with an oligodendrocyte cell line were performed to reveal the impact on survival and differentiation. Circulating lymphocytes from MS patients displayed increased CD6 levels, associated with heightened activation and proliferation features in CD4+ memory T cells. In brain barrier assays, migrated T cells exhibited higher CD6 expression than non-migrated cells. CD6 blockade with itolizumab selectively reduced memory and cytotoxic T cell diapedesis across hCMEC/D3 monolayers, while maintaining naïve and regulatory T cell migration, by disrupting interaction with ALCAM but not CD318, attenuating cytokine-driven upregulation of endothelial adhesion molecules, and strengthening BBB integrity. Itolizumab limited the retention and acquisition of a disease-promoting CD69+TRM phenotype in migrated CD4+ T cells, while attenuating their activity in the CNS, thereby promoting oligodendrocyte survival and differentiation. These findings provide mechanistic support for targeting CD6 in MS with itolizumab as a promising therapeutic strategy to reduce neuroinflammation and pathogenic T cell accumulation in the CNS.

COVID-19 management in patients with comorbid conditions.

Sanyaolu Adekunle A, Okorie Chuku C, Marinkovic Aleksandra A, Prakash Stephanie S et al.

The novel coronavirus disease 2019 (COVID-19) causes serious respiratory illness and related disorders. Vulnerable populations, including those with chronic obstructive pulmonary disease, heart disease, diabetes, chronic kidney disease, obesity, and the elderly, face an increased risk of severe complications. As the pandemic evolves, various diagnostic techniques are available to detect severe acute respiratory distress syndrome (SARS-CoV-2), including clinical presentation, rapid antigen/antibody testing, molecular testing, supplemental laboratory analysis, and imaging. Based on peer-reviewed data, treatment options include convalescent plasma transfusion, corticosteroids, antivirals, and immunomodulatory medications. Convalescent plasma therapy, historically used in outbreaks like Middle East respiratory syndrome, Ebola, and SARS, is suggested by the World Health Organization for critically ill COVID-19 patients when vaccines or antiviral drugs are unavailable. Neutralizing antibodies in convalescent plasma help control viral load and improve patient outcomes, especially when administered early, though effectiveness varies. The United States Food and Drug Administration has authorized its emergency use for severe COVID-19 cases, but potential risks such as transfusion reactions and transfusion-related acute lung injury require further investigation to establish definitive efficacy. Antiviral agents like Remdesivir, an adenosine nucleotide analog, inhibit viral RNA polymerase and have shown efficacy in reducing COVID-19 severity, leading to its emergency use authorization for hospitalized patients. Other antivirals like ritonavir, lopinavir, and umifenovir disrupt viral replication and entry, but their effectiveness against SARS-CoV-2 remains under investigation. Dexamethasone, a corticosteroid, has been used in critically ill COVID-19 patients to reduce inflammation and prevent respiratory failure, as shown in the RECOVERY trial. Other immunosuppressants like ruxolitinib, baricitinib, and colchicine help modulate the immune response, reducing cytokine storms and inflammation-related complications. However, corticosteroids carry risks such as hyperglycemia, immunosuppression, and delayed viral clearance, requiring careful administration. Systematic reviews of clinical studies revealed that hydroxychloroquine with or without azithromycin did not decrease viral load nor reduce the severity of symptoms, but increased mortality among acutely hospitalized patients. There was no improvement in patients' clinical conditions after 15 days compared to standard treatment. The United States Food and Drug Administration has revoked the authorization for the use of hydroxychloroquine in COVID-19 patients due to the null benefit-risk balance. Monoclonal antibodies like itolizumab, gimsilumab, sarilumab, and tocilizumab are being studied for their ability to reduce the severe inflammatory response in COVID-19 patients, particularly cytokine release syndrome and acute respiratory distress syndrome. These antibodies target specific immune pathways to decrease pro-inflammatory cytokines, with some showing promising results in clinical trials, though their use remains under investigation. The Clustered Regularly Interspaced Short Palindromic Repeats/Cas13 family of enzymes, sequenced from many COVID-19-positive patients, can potentially inhibit SARS-CoV-2 replication, cleave the RNA genome, and aid in the amplification of the genome assay. Cas13 can also target emerging pathogens via an adeno-associated virus vector when delivered to the infected lungs. In addition to pharmacological agents, vaccines effectively prevent symptomatic infection, reduce hospitalizations, minimize mortality rates, and ultimately reduce the severity of the disease. This paper aims to explore the management of patients with underlying conditions who present with COVID-19 to lessen the burden on healthcare systems.

Itolizumab regulates activating and inhibitory signals on effector cells, improving their cytotoxicity against CD318+ tumor cell lines.

González Muñoz Cynthia C, Álvarez Arzola Rydell R, Calvo Pérez Adanays A, Frometa Campanón Milagro de la Caridad MC et al.

The CD6-CD318 axis has emerged as a potential target for immuno-oncology. Recent work has shown that blocking the CD6-CD318 interaction with a murine anti-human CD6 antibody increases lymphocyte cytotoxicity. However, several studies have demonstrated the drawbacks associated with the clinical use of murine antibodies and the variability among anti-CD6 antibodies. Therefore, evidence that the first-in-class humanized anti-human CD6 antibody itolizumab could be used for cancer immunotherapy may be a breakthrough in developing an antitumor clinical approach. Phenotypic and functional characterization of peripheral blood mononuclear cells (PBMCs) from healthy donors after challenge with CD318+ cell lines was performed by flow cytometry. In addition, IFNγ was determined by ELISA in culture supernatants. Immunohistochemical analyses of breast tumor samples were also performed. Here, we provide evidence supporting the rationale for itolizumab in cancer immunotherapy. The blockade of the CD6-CD318 interaction by itolizumab increases the cytotoxic capacity of CD8 T and NK cells over CD318+ tumor lines, reverses the NKG2A/NKG2D ratio, and increases granzyme B and IFNγ production. Itolizumab also regulates immune responses by downregulating CD5 expression and upregulating PD-1 and CTLA-4 inhibitory receptors on lymphocytes, which contribute to reducing exacerbated responses and additively enhancing CD318+ tumor cell cytotoxicity when combined with other immunocheckpoint inhibitors. In addition, we report that CD6-CD318 interaction inhibits lymphocyte proliferation and survival while downregulating CD6 expression on lymphocytes in vitro and in human breast cancer tissue samples, reinforcing the role of the CD6-CD318 axis as an immune checkpoint and highlighting the potential of itolizumab as an immune checkpoint inhibitor. Taken together, our results provide the first evidence linking the blocking of the CD6-CD318 axis by itolizumab with the potentiation of functional properties of lymphocytes, highlighting itolizumab as a novel promising immunotherapy for CD318+ tumors and supporting the relevance of new combinatorial therapies with checkpoint inhibitors.

Corrigendum to: Comparative evaluation of tocilizumab and itolizumab for treatment of severe COVID-19 in India: a retrospective cohort study.

Kumar Abhyuday A, Kumar Neeraj N, Pattanayak Arunima A, Kumar Ajeet A et al.