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.
Background
This study investigated the safety and efficacy of an anti–CTLA‐4 monoclonal antibody (CS1002) as monotherapy and in combination with an anti–PD‐1 monoclonal antibody (CS1003) in patients ...with advanced/metastatic solid tumors.
Methods
The phase 1 study involved phase 1a monotherapy dose‐escalation (part 1) and phase 1b combination therapy dose escalation (part 2) and expansion (part 3). Various dosing schedules of CS1002 (0.3, 1, or 3 mg/kg every 3 weeks, or 3 mg/kg every 9 weeks) were evaluated with 200 mg CS1003 every 3 weeks in part 3.
Results
Parts 1, 2, and 3 included a total of 13, 18, and 61 patients, respectively. No dose‐limiting toxicities or maximum tolerated doses were observed. Treatment‐related adverse events (TRAEs) were reported in 30.8%, 83.3%, and 75.0% of patients in parts 1, 2, and 3, respectively. Grade ≥3 TRAEs were experienced by 15.4%, 50.0%, and 18.3% of patients in each part. Of 61 patients evaluable for efficacy, 23 (37.7%) achieved objective responses in multiple tumor types. Higher objective response rates were observed with conventional and high‐dose CS1002 regimens (1 mg/kg every 3 weeks or 3 mg/kg every 9 weeks) compared to low‐dose CS1002 (0.3 mg/kg every 3 weeks) in microsatellite instability‐high/mismatch repair‐deficient tumors, melanoma, and hepatocellular carcinoma (50.0% vs. 58.8%, 14.3% vs. 42.9%, and 0% vs. 16.7%).
Conclusion
CS1002, as monotherapy, and in combination with CS1003, had a manageable safety profile across a broad dosing range. Promising antitumor activities were observed in patients with immune oncology (IO)‐naive and IO‐refractory tumors across CS1002 dose levels when combined with CS1003, supporting further evaluation of this treatment combination for solid tumors.
Plain Language Summary
CS1002 is a human immunoglobulin (Ig) G1 monoclonal antibody that blocks the interaction of CTLA‐4 with its ligands and increases T‐cell activation/proliferation. CS1003, now named nofazinlimab, is a humanized, recombinant IgG4 monoclonal antibody that blocks the interaction between human PD‐1 and its ligands.
In this original article, we determined the safety profile of CS1002 as monotherapy and in combination with CS1003. Furthermore, we explored the antitumor activity of the combination in anti–programmed cell death protein (ligand)‐1 (PD‐L1)‐naive microsatellite instability‐high/mismatch repair‐deficient (MSI‐H/dMMR) pan tumors, and anti–PD‐(L)1‐refractory melanoma and hepatocellular carcinoma (HCC).
CS1002 in combination with CS1003 had manageable safety profile across a broad dosing range and showed promising antitumor activities across CS1002 dose levels when combined with CS1003. This supports further assessment of CS1002 in combination with CS1003 for the treatment of solid tumors.
This was a phase 1a/1b, dose‐escalation and dose‐expansion study evaluating the safety and efficacy of an anti–CTLA‐4 monoclonal antibody (CS1002) as monotherapy and in combination with an anti–PD‐1 monoclonal antibody (CS1003/nofazinlimab), in patients with advanced/metastatic solid tumors. Promising antitumor activities were observed in heavily pretreated patients with immune oncology (IO)‐naive and IO‐refractory tumors across CS1002 dose levels when combined with CS1003, which supports further assessment of CS1002 in combination with CS1003 for the treatment of solid tumors.
Nemolizumab, an anti–IL-31 receptor A mAb, improved pruritus, dermatitis, and sleep in adults with moderate-to-severe atopic dermatitis that was inadequately controlled by topical treatments in a ...phase II, 12-week, randomized, double-blind, placebo-controlled study (part A; NCT01986933).
We sought to assess the long-term efficacy and safety of nemolizumab injected subcutaneously every 4 weeks (Q4W) or every 8 weeks (Q8W) in a 52-week, double-blind extension (part B).
During part B, patients continued the previous nemolizumab dose (0.1, 0.5, or 2.0 mg/kg Q4W or 2.0 mg/kg Q8W). Part B end points included percentage improvement from baseline in pruritus visual analog scale and dermatitis scores (including the Eczema Area and Severity Index).
Overall, 216 of 264 patients completed part A, and 191 entered part B; 131 completed part B. In 153 patients randomized to nemolizumab in part A, improvement from baseline in pruritus visual analog scale score was maintained/increased from weeks 12 to 64, with greatest improvement in the 0.5-mg/kg Q4W group (percentage change from baseline at week 64: −73.0, −89.6, −74.7, and −79.1 in the 0.1-, 0.5-, and 2.0-mg/kg Q4W and 2.0-mg/kg Q8W groups, respectively). Improvement from baseline in dermatitis scores was also maintained/increased to week 64 (percentage change in Eczema Area and Severity Index score: −68.5, −75.8, −78.9, and −69.3 in the 0.1-, 0.5-, and 2.0-mg/kg Q4W and 2.0-mg/kg Q8W groups, respectively). Over 64 weeks, 83% to 89% had 1 or more adverse events, with no new safety concerns identified.
Nemolizumab for up to 64 weeks was efficacious and overall well tolerated in patients with moderate-to-severe atopic dermatitis inadequately controlled by topical therapy.
Background
Recurrent head and neck squamous cell carcinoma (rHNSCC) represents a significant global health burden with an unmet medical need. In this study we determined the safety and efficacy of ...RM‐1929 photoimmunotherapy in patients with heavily pretreated rHNSCC.
Methods
RM‐1929 (anti‐EGFR–IR700 dye conjugate) was infused, followed by tumor illumination. We evaluated safety, tumor response, and pharmacokinetics.
Results
Nine patients were enrolled in Part 1 (dose‐finding) and 30 patients in Part 2 (safety and efficacy). No dose‐limiting toxicities were experienced in Part 1; 640 mg/m2 with fixed light dose (50 J/cm2 or 100 J/cm) was recommended for Part 2. Adverse events (AEs) in Part 2 were mostly mild to moderate but 19 (63.3%) patients had AE ≥Grade 3, including 3 (10.0%) with serious AEs leading to death (not treatment related). Efficacy in Part 2: unconfirmed objective response rate (ORR) 43.3% (95% CI 25.46%–62.57%); confirmed ORR 26.7% (95% CI 12.28%–45.89%); median overall survival 9.30 months (95% CI 5.16–16.92 months).
Conclusions
Treatment was well tolerated. Responses and survival following RM‐1929 photoimmunotherapy in heavily pretreated patients with rHNSCC were clinically meaningful and warrant further investigation.
Clinical Trial Information
NCT02422979.
The approval of the first two monoclonal antibodies targeting CD38 (daratumumab) and SLAMF7 (elotuzumab) in late 2015 for treating relapsed and refractory multiple myeloma (RRMM) was a critical ...advance for immunotherapies for multiple myeloma (MM). Importantly, the outcome of patients continues to improve with the incorporation of this new class of agents with current MM therapies. However, both antigens are also expressed on other normal tissues including hematopoietic lineages and immune effector cells, which may limit their long-term clinical use. B cell maturation antigen (BCMA), a transmembrane glycoprotein in the tumor necrosis factor receptor superfamily 17 (TNFRSF17), is expressed at significantly higher levels in all patient MM cells but not on other normal tissues except normal plasma cells. Importantly, it is an antigen targeted by chimeric antigen receptor (CAR) T-cells, which have already shown significant clinical activities in patients with RRMM who have undergone at least three prior treatments, including a proteasome inhibitor and an immunomodulatory agent. Moreover, the first anti-BCMA antibody-drug conjugate also has achieved significant clinical responses in patients who failed at least three prior lines of therapy, including an anti-CD38 antibody, a proteasome inhibitor, and an immunomodulatory agent. Both BCMA targeting immunotherapies were granted breakthrough status for patients with RRMM by FDA in Nov 2017. Other promising BCMA-based immunotherapeutic macromolecules including bispecific T-cell engagers, bispecific molecules, bispecific or trispecific antibodies, as well as improved forms of next generation CAR T cells, also demonstrate high anti-MM activity in preclinical and even early clinical studies. Here, we focus on the biology of this promising MM target antigen and then highlight preclinical and clinical data of current BCMA-targeted immunotherapies with various mechanisms of action. These crucial studies will enhance selective anti-MM response, transform the treatment paradigm, and extend disease-free survival in MM.
Summary
We examined the assay formats used to detect anti‐drug antibodies (ADA) in clinical studies of the anti‐tumour necrosis factor (TNF) monoclonal antibodies adalimumab and infliximab in chronic ...inflammatory disease and their potential impact on pharmacokinetic and clinical outcomes. Using findings of a recent systematic literature review of the immunogenicity of 11 biological/biosimilar agents, we conducted an ancillary qualitative review of a subset of randomized controlled trials and observational studies of the monoclonal antibodies against anti‐TNF factor adalimumab and infliximab. Among studies of adalimumab and infliximab, the immunoassay method used to detect antibodies was reported in 91 of 111 (82%) and 154 of 206 (75%) adalimumab and infliximab studies, respectively. In most adalimumab and infliximab studies, an enzyme‐linked immunosorbent assay or radioimmunoassay was used 85 of 91 (93%) and 134 of 154 (87%), respectively. ADA incidence varied widely among assays and inflammatory diseases (adalimumab, 0–87%; infliximab, 0–79%). Pharmacokinetic and clinical outcomes were only reported for ADA‐positive patients in 38 of 91 (42%) and 61 of 154 (40%) adalimumab and infliximab studies, respectively. Regardless of assay format or biological used, ADA formation was associated with lower serum concentrations, reduced efficacy and elevated rates of infusion‐related reactions. Consistent with previous recommendations to improve interpretation of immunogenicity data for biologicals, greater consistency in reporting of assay methods and clinical consequences of ADA formation may prove useful. Additional standardization in immunogenicity testing and reporting, application of modern, robust assays that satisfy current regulatory expectations and implementation of international standards for marketed products may help to improve our understanding of the impact of immunogenicity to biologics.
We conducted a literature review to examine the assay formats used to detect anti‐drug antibodies (ADA) in clinical studies of the anti‐TNF monoclonal antibodies adalimumab and infliximab in chronic inflammatory disease. Enzyme‐linked immunosorbent assays and radioimmunoassays were used in 93% and 87% of adalimumab and infliximab studies, respectively. ADA incidence varied from 0 to 87% in adalimumab studies and 0 to 79% in infliximab studies across assays and inflammatory diseases. The presence of ADA was associated with reduced serum concentrations and efficacy and increased rates of infusion‐related reactions, independent of the assay format and biologic used.
► Monoclonal antibodies (mAbs) are essential drugs for treatment of various diseases. ► The heterogeneity of mAbs is significant and should be well characterized. ► Reversed-phase liquid ...chromatography is a powerful strategy for mAbs analysis. ► Capillary-zone electrophoresis is a good option, because of its MS compatibility. ► Adsorption of mAbs is a major concern with both electrophoresis and chromatography.
Recombinant monoclonal antibodies (mAbs) have become particularly relevant for the treatment of autoimmune diseases or cancers. Because of their inherent complexity and for safety reasons, there is a need to develop powerful analytical methods to provide detailed characterizations of mAbs.
The aim of the present review is to detail the state-of-the-art of analytical strategies for mAb characterization. It focuses on the most important separation techniques used in this field, specifically, the chromatographic and electrophoretic approaches and their combination with mass spectrometry (MS). Thanks to recent improvements in separation science and MS devices, mAbs can be analyzed more easily. However, there is still a need to find new approaches that avoid adsorption issues.
As an important proangiogenic factor, platelet-derived growth factor (PDGF) and its receptor PDGFR are highly expressed in a variety of tumors, fibrosis, cardiovascular and neurodegenerative ...diseases. Targeting the PDGF/PDGFR pathway is therefore a promising therapeutic strategy. At present, a variety of PDGF/PDGFR targeted drugs with potential therapeutic effects have been developed, mainly including PDGF agonists, inhibitors targeting PDGFR and proteolysis targeting chimera (PROTACs). This review clarifies the structure, biological function and disease correlation of PDGF and PDGFR, and it discusses the current status of PDGFR-targeted drugs, so as to provide a reference for subsequent research.
The coronavirus disease 2019 (COVID-19) is currently representing a global health threat especially for fragile individuals, such as cancer patients. It was demonstrated that cancer patients have an ...increased risk of developing a worse symptomatology upon severe acute respiratory syndrome associated coronavirus-2 (SARS-CoV-2) infection, often leading to hospitalization and intensive care. The consequences of this pandemic for oncology are really heavy, as the entire healthcare system got reorganized. Both oncologists and cancer patients are experiencing rescheduling of treatments and disruptions of appointments with a concurrent surge of fear and stress. In this review all the up-to-date findings, concerning the association between COVID-19 and cancer, are reported. A remaining very debated question regards the use of an innovative class of anti-cancer molecules, the immune checkpoint inhibitors (ICIs), given their modulating effects on the immune system. For that reason, administration of ICIs to cancer patients represents a question mark during this pandemic, as its correlation with COVID-19-associated risks is still under investigation. Based on the mechanisms of action of ICIs and the current evidence, we suggest that ICIs not only can be safely administered to cancer patients, but they might even be beneficial in COVID-19-positive cancer patients, by exerting an immune-stimulating action.
Anti-KIR monoclonal antibodies (mAbs) can enhance the antitumor responses of natural killer (NK) cells. We evaluated the safety of the anti-KIR2D mAb lirilumab in patients with various cancers.
...Thirty-seven patients with hematological malignancies (
= 22) or solid tumors (
= 15) were included in the study. Dose escalation (0.015 to 10 mg/kg) was conducted following a 3 + 3 design. Patients were scheduled to receive four cycles of treatment. In a second (extension) phase 17 patients were treated at 0.015 (
= 9) or 3 mg/kg (
= 8).
No dose-limiting toxicity was recorded. The most frequent lirilumab-related adverse events were pruritus (19%), asthenia (16%), fatigue (14%), infusion-related reaction (14%), and headache (11%), mostly mild or moderate. Pharmacokinetics was dose-dependent and linear, with minimal accumulation resulting from the 4-weekly repeated administrations. Full KIR occupancy (>95%) was achieved with all dosages, and the duration of occupancy was dose-related. No significant changes were observed in the number or distribution of lymphocyte subpopulations, nor was any reduction in the distribution of KIR2D-positive NK cells.
This phase 1 trial demonstrated the satisfactory safety profile of lirilumab up to doses that enable full and sustained blockade of KIR.
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