Aponermin: First Approval

Declarations Funding The preparation of this review was not supported by any external funding. Authorship and Conflict of interest During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the authors on the basis of scientific completeness and accuracy. Sohita Dhillon is a contracted employee of Adis International Ltd/Springer Nature, and declares no relevant conflicts of interest. All authors contributed to the review and are responsible for the article content. Ethics approval, Consent to participate, Consent to publish, Availability of data and material, Code availability not applicable. Additional information about this Adis Drug Review can be found here. Abstract Aponermin (沙艾特) is a recombinant circularly permuted human tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) developed by Beijing Sunbio Biotech (a wholly owned subsidiary of Wuhan Hiteck Biological Pharma CO., LTD) for the treatment of multiple myeloma. Aponermin binds to and activates the death receptors 4 and/or 5 on tumour cells, triggering intracellular caspase reactions and inducing apoptosis, thereby exerting antitumor effects. In November 2023, aponermin in combination with thalidomide and dexamethasone received its first approval in China for the treatment of patients with relapsed or refractory multiple myeloma who have received at least two prior therapies. This article summarizes the milestones in the development of aponermin leading to this first approval for relapsed or refractory multiple myeloma. © Springer Nature Switzerland AG 2023</p

Meningococcal Quadrivalent Tetanus Toxoid Conjugate Vaccine (MenACWY-TT; Nimenrix®): A Review

<div>Compliance with Ethical Standards</div><div><br></div><div><i>Funding:</i> The preparation of this review was not supported by any external funding. </div><div><br></div><div><i>Conflicts of interest</i>: Sohita Dhillon is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.</div><div><br></div><div>Additional information about this Adis Drug Review can be found <b><a href="http://www.springer.com/gp/adis/products-services/adis-journals-newsletters/adis-drug-reviews">here</a>.</b></div><div><br></div><div>Abstract</div><div><br></div><div>MenACWY-TT (Nimenrix®) is a quadrivalent meningococcal tetanus toxoid conjugate vaccine licensed in Europe for active immunisation of individuals aged ≥6 weeks against invasive disease caused by Neisseria meningitidis capsular groups A, C, W and Y. MenACWY-TT is the first quadrivalent conjugate vaccine to be approved in Europe for use in infants as young as 6 weeks of age. Numerous phase II–IIIb clinical studies showed that intramuscular MenACWY-TT administered as primary or booster vaccination was highly immunogenic for all four vaccine capsular groups and had an acceptable reactogenicity profile in individuals aged 6 weeks to ≥56 years. MenACWY-TT is as immunogenic and safe as other previously licensed monovalent capsular group C or quadrivalent capsular groups A, C, W and Y meningococcal vaccines and can be coadministered with other routine vaccines without adversely affecting the immunogenicity or safety profiles of either vaccine. Current data indicate that primary and booster vaccination with MenACWY-TT is a valuable and safe option for broadening meningococcal protection against four capsular groups across a broad age range, starting as early as 6 weeks of age. Access to the full article can be found<b> <a href="https://link.springer.com/article/10.1007/s40265-017-0828-8">here</a>.</b></div><div><br></div><div>© Springer International Publishing AG, part of Springer Nature 2017</div

Repotrectinib: First Approval

Declarations Funding The preparation of this review was not supported by any external funding. Authorship and Conflict of interest During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the authors on the basis of scientific completeness and accuracy. Sohita Dhillon is a contracted employee of Adis International Ltd/Springer Nature, and declares no relevant conflicts of interest. All authors contributed to the review and are responsible for the article content. Ethics approval, Consent to participate, Consent to publish, Availability of data and material, Code availability not applicable. Additional information about this Adis Drug Review can be found here. Abstract Repotrectinib (AUGTYRO™) is a next-generation, oral, small-molecule kinase inhibitor of proto-oncogene tyrosine-protein kinase ROS1 (ROS1) and tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC. It is being developed by Turning Point Therapeutics, a wholly owned subsidiary of Bristol-Myers Squibb (BMS), for the treatment of locally advanced or metastatic solid tumours, including non-small cell lung cancer (NSCLC). Repotrectinib is a next-generation tyrosine kinase inhibitor rationally designed to inhibit ROS1 and TRK fusion, including in the presence of resistance mutations such as solvent-front mutations. In November 2023, repotrectinib received its first approval in the USA for the treatment of adults with locally advanced or metastatic ROS1-positive NSCLC. Repotrectinib is under regulatory review in China and the EU for NSCLC. Clinical studies of repotrectinib are ongoing in several countries in patients with NSCLC and other solid tumours (including primary central nervous system cancer) across both adult and paediatric patient populations. In addition, preclinical investigation of repotrectinib in multiple myeloma is underway in the USA. This article summarizes the milestones in the development of repotrectinib leading to this first approval for the treatment of locally advanced or metastatic ROS1-positive NSCLC.  © Springer Nature Switzerland AG 2023</p

Tofacitinib: A Review in Rheumatoid Arthritis

<div>Compliance with Ethical Standards</div><div><br></div><div><i>Funding:</i> The preparation of this review was not supported by any external funding.</div><div><br></div><div><i>Conflicts of interest: </i>Sohita Dhillon is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.</div><div><br></div><div>Additional information about this Adis Drug Review can be found <a href="http://www.springer.com/gp/adis/products-services/adis-journals-newsletters/adis-drug-reviews"><b>here</b></a>.</div><div><br></div><div>Abstract</div><div><br></div><div>Tofacitinib (Xeljanz®) is a potent, selective JAK inhibitor that preferentially inhibits Janus kinase (JAK) 1 and JAK3. In the EU, oral tofacitinib 5 mg twice daily is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have responded inadequately to, or who are intolerant of, one or more DMARDs. Several clinical studies of ≤24 months’ duration showed that tofacitinib monotherapy (as first- or second-line treatment) and combination therapy with a conventional synthetic DMARD (as second- or third-line treatment) was effective in reducing signs and symptoms of disease and improving health-related quality of life (HR-QOL), with benefits sustained during long-term therapy (≤96 months). Tofacitinib monotherapy inhibited progression of structural damage in methotrexate-naïve patients during ≤24 months’ treatment, with beneficial effects also seen in patients receiving tofacitinib plus methotrexate as second-line therapy for 12 months. Tofacitinib was generally well tolerated during ≤114 months’ treatment, with most adverse events of mild or moderate severity. The tolerability profile of tofacitinib was generally similar to that of biological DMARDs (bDMARDs), with infections and infestations the most common (AEs) in tofacitinib recipients. However, the incidence of herpes zoster (HZ) was higher with tofacitinib than in the general RA population, although infections were clinically manageable. When added to background methotrexate, tofacitinib was noninferior to adalimumab in terms of efficacy, and both combination therapies had generally similar tolerability profiles. Although additional comparative studies are needed to more definitively position tofacitinib relative to bDMARDs and other targeted synthetic DMARDs, current evidence indicates that oral tofacitinib is a useful option for the treatment of patients with RA. Access to the full article can be found <b><a href="https://link.springer.com/article/10.1007/s40265-017-0835-9">here</a>.</b></div><div><br></div><div>© Springer International Publishing AG, part of Springer Nature 2017</div

Nintedanib in advanced NSCLC of adenocarcinoma histology: a profile of its use in the EU

<div><i>Funding:</i> The preparation of this review was not supported by any external funding.</div><div><br></div><div><i>Conflicts of interest: </i>S. Dhillon is an employee of Adis/Springer, is responsible for the article content and declares no conflicts of interest.</div><div><br></div><div>Additional information about this Adis Drug Review can be found <b><a href="http://www.springer.com/gp/adis/products-services/adis-journals-newsletters/adis-drug-reviews">here</a>.</b></div><div><br></div><div>Abstract</div><div><br></div><div>Nintedanib (Vargatef®) is a triple angiokinase inhibitor that potently blocks the proangiogenic pathways mediated by vascular endothelial growth factor receptors, platelet-derived growth factor receptors and fibroblast growth factor receptors. In the phase 3 LUME-Lung 1 study in patients with advanced non-small cell lung cancer (NSCLC), the subgroup of patients with adenocarcinoma histology who have progressed after first line chemotherapy experienced a significant improvement in progression-free and overall survival with oral nintedanib + docetaxel relative to placebo + docetaxel, with greater benefits seen in patients with rapidly progressing disease. Nintedanib is the first antiangiogenic agent to have shown a survival benefit in the second-line treatment of these patients. Nintedanib combination therapy has a generally manageable tolerability profile. Access to the full article can be found <a href="https://link.springer.com/article/10.1007/s40267-018-0481-7"><b>here</b></a>.</div><div><br></div><div>© Springer International Publishing AG, part of Springer Nature 2018</div><div><br></div

Upregulation of KIR expression on murine bone marrow cells by paraformaldehyde fixed tumor cells

We have previously shown that the activation of mouse spleen NK cells by IL2 is markedly boosted if paraformaldehyde fixed tumor target cells are added during the activation phase. In the present study, we have shown that such a boosting effect is not seen if mouse bone marrow (BM) cells are used instead of spleen cells. Addition of fixed tumor cells (1:100 ratio of tumor cells to BM cells) however resulted in a marked increase in the expression of Ly49 molecules on BM cells. The enhancement of Ly49 expression was not seen if fixed allogeneic BM cells were added, suggesting that Ly49 upregulation was tumor specific. Expression of Ly49A as well as Ly49C isotypes were augmented by fixed tumor cells. Moreover, increased Ly49 expression was seen on cell populations expressing TCRβ as well as NK1.1 markers. These results indicate that exposure to tumor cells may be an important factor regulating KIR expression on NK and T cells.Implications of these results are discussed

Tumor specific boosting of IL-2 induced NK activation by paraformaldehyde fixed tumor cells

NK activation in C57Bl/6 mouse spleen cells was carried out with IL-2 in the presence or absence of paraformaldehyde fixed YAC tumor cells. Generation of anti-YAC cytolytic activity was markedly higher when activation was carried out in the presence of fixed tumor cells. In addition the cytotoxic effector cells generated were resistant to anti-Thy-1+C treatment, indicating that the effector cells were not T lymphocytes. IL-2 activation of NK cells was compared When fixed YAC or EL4 tumor cells were added during the IL-2 activation phase, it was found that the addition of either of these tumor cells significantly boosted the levels of cytotoxic activity generated against both targets. Significantly higher anti-YAC cytotoxic activity was however generated when fixed YAC cells instead of EL4 cells were present during the activation phase. Similarly, significantly greater cytolytic activity was generated against EL4 cells, when fixed EL4 rather than YAC cells were present during the activation phase. Addition of paraformaldehyde fixed syngeneic or allogenic spleen cells instead of tumor cells, did not boost NK activation in response to IL-2, indicating that the boosting of NK activation did not result from exposure to alloantigens during the activation phase. These results indicate that an exposure to tumor cells during IL-2 activation phase, may boost the activation of NK cells in a tumor specific manner