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11 pages, 2300 KiB

Open AccessArticle

Enhancing Therapeutic Drug Monitoring in Inflammatory Bowel Disease: A Comparative Analysis of Rapid Point-of-Care Infliximab, Adalimumab and Anti-Drug Antibodies’ Determination against ELISA

by Francisco José Toja-Camba, Laura García-Quintanilla, Lorena Rodríguez-Martinez, Julia Tomine, Francisco Cajade-Pascual, Carolina Feitosa, Irene Zarra-Ferro, Manuel Barreiro-De-Acosta, Jaime González-López, Cristina Mondelo-García and Anxo Fernández-Ferreiro

Pharmaceutics 2023, 15(11), 2615; https://doi.org/10.3390/pharmaceutics15112615 - 11 Nov 2023

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Abstract

The introduction of point-of-care (POC) assays into clinical practice in patients with inflammatory disease enables on-demand therapeutic decision making. The aim of this study was to compare the POC test Quantum blue (Bühlmann Laboratories) for infliximab (IFX), adalimumab (ADL), and its anti-drug antibodies [...] Read more.

The introduction of point-of-care (POC) assays into clinical practice in patients with inflammatory disease enables on-demand therapeutic decision making. The aim of this study was to compare the POC test Quantum blue (Bühlmann Laboratories) for infliximab (IFX), adalimumab (ADL), and its anti-drug antibodies with the traditional ELISA assay (Promonitor). A total of 200 serum samples were analyzed. Samples were classified into the following three different groups; sub-therapeutic range (IFX < 3 μg/mL and ADL < 5 μg/mL); therapeutic range (IFX: 3–7 μg/mL and ADL: 5–12 μg/mL) and supra-therapeutic range (IFX levels > 7 μg/mL and ADL levels > 12 μg/mL). Significant higher values were measured using the POC test (p < 0.001) for IFX results but no differences in ADL trough levels were observed (p = 0.3101). Spearman’s correlation indicated a good correlation between the two assays (rs = 0.88 for ADL and rs = 0.93 for IFX), and McNemar’s test revealed significant differences (p = 0.016) when classifying IFX samples between therapeutic and supra-therapeutic ranges but no significant differences were found among the other ranges for either IFX or ADL. These results show that we should be cautious when using these rapid measurement methods, and new targets should probably be defined for IFX when using this new analytical method. Full article

(This article belongs to the Special Issue Recent Advances in Therapeutic Antibody)

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17 pages, 4971 KiB

Open AccessArticle

A Novel Dual-Payload ADC for the Treatment of HER2+ Breast and Colon Cancer

by Candice Maria Mckertish and Veysel Kayser

Pharmaceutics 2023, 15(8), 2020; https://doi.org/10.3390/pharmaceutics15082020 - 26 Jul 2023

Cited by 2 | Viewed by 2352

Abstract

Antibody-drug conjugates (ADCs) have demonstrated a great therapeutic potential against cancer due to their target specificity and cytotoxicity. To exert a maximum therapeutic effect on cancerous cells, we have conjugated two different payloads to different amino acids, cysteines (cys) and lysines (lys), on [...] Read more.

Antibody-drug conjugates (ADCs) have demonstrated a great therapeutic potential against cancer due to their target specificity and cytotoxicity. To exert a maximum therapeutic effect on cancerous cells, we have conjugated two different payloads to different amino acids, cysteines (cys) and lysines (lys), on trastuzumab, which is a humanised anti-HER2 monoclonal antibody. First, trastuzumab was conjugated with monomethyl auristatin E (MMAE), an antimitotic agent, through a cleavable linker (Val-Cit) to prepare ADC (Tmab-VcMMAE). Then, the ADC (Tmab-VcMMAE) was conjugated with a second antimitotic agent, Mertansine (DM1), via a non-cleavable linker Succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) to form a dual conjugate (Tmab-VcMMAE-SMCC-DM1). Our results indicated that the dual-payload conjugate, Tmab-VcMMAE-SMCC-DM1, had a synergistic and superior cytotoxic effect compared to trastuzumab alone. Ultimately employing a dual conjugation approach has the potential to overcome treatment-resistance and tumour recurrences and could pave the way to employ other payloads to construct dual (or multiple) payload complexes. Full article

(This article belongs to the Special Issue Recent Advances in Therapeutic Antibody)

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17 pages, 3401 KiB

Open AccessArticle

The Screening of Broadly Neutralizing Antibodies Targeting the SARS-CoV-2 Spike Protein by mRNA Immunization in Mice

by Zhiyin An, Yu Zhang, Xiang Yu, Jia Xia, Yanan Yin, Guoming Li, Jing Lu, Xuemei Fan and Yingjie Xu

Pharmaceutics 2023, 15(5), 1412; https://doi.org/10.3390/pharmaceutics15051412 - 05 May 2023

Viewed by 1682

Abstract

Neutralizing antibodies (nAbs), the popular antiviral drugs used for the treatment of COVID-19, are effective in reducing viral load and hospitalization. Currently, most nAbs are screened from convalescent or vaccinated individuals through single B-cell sequencing which requires cutting-edge facilities. Moreover, owing to the [...] Read more.

Neutralizing antibodies (nAbs), the popular antiviral drugs used for the treatment of COVID-19, are effective in reducing viral load and hospitalization. Currently, most nAbs are screened from convalescent or vaccinated individuals through single B-cell sequencing which requires cutting-edge facilities. Moreover, owing to the rapid mutation of SARS-CoV-2, some approved nAbs are no longer effective. In the present study, we designed a new approach to acquiring broadly neutralizing antibodies (bnAbs) from mRNA-vaccinated mice. Using the flexibility and speed of mRNA vaccine preparation, we designed a chimeric mRNA vaccine and sequential immunization strategies to acquire bnAbs in mice within a short period. By comparing different vaccination orders, we found that the initially administered vaccine had a greater effect on the neutralizing potency of mouse sera. Ultimately, we screened a strain of bnAb that neutralized wild-type, Beta, and Delta SARS-CoV-2 pseudoviruses. We synthesized the mRNAs of the heavy and light chains of this antibody and verified its neutralizing potency. This study developed a new strategy to screen for bnAbs in mRNA-vaccinated mice and identified a more effective immunization strategy for inducing bnAbs, providing valuable insights for future antibody drug development. Full article

(This article belongs to the Special Issue Recent Advances in Therapeutic Antibody)

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11 pages, 660 KiB

Open AccessArticle

Adalimumab Serum Concentrations, Clinical and Endoscopic Disease Activity in Crohn’s Disease: A Cross-Sectional Multicentric Latin American Study

by Letícia Rodrigues de Souza, Daniela Oliveira Magro, Fábio Vieira Teixeira, Rogério Serafim Parra, Eron Fábio Miranda, Omar Féres, Rogério Saad-Hossne, Giedre Soares Prates Herrerias, Renato Mitsunori Nisihara, Claudio Saddy Rodrigues Coy, Ligia Yukie Sassaki and Paulo Gustavo Kotze

Pharmaceutics 2023, 15(2), 586; https://doi.org/10.3390/pharmaceutics15020586 - 09 Feb 2023

Cited by 2 | Viewed by 1159

Abstract

Despite some variability in ideal serum Adalimumab (ADA) concentrations, there is increasing evidence that higher concentrations of anti-TNF-α agents can be associated with sustained efficacy, and low or undetectable levels may lead to loss of response. This study aims to correlate serum ADA [...] Read more.

Despite some variability in ideal serum Adalimumab (ADA) concentrations, there is increasing evidence that higher concentrations of anti-TNF-α agents can be associated with sustained efficacy, and low or undetectable levels may lead to loss of response. This study aims to correlate serum ADA concentrations with clinical and endoscopic activity in patients with Crohn’s disease (CD). A cross-sectional and multicentric study was performed with patients with CD, who used ADA for at least 24 weeks. Patients were allocated into groups according to the presence of clinical or endoscopic disease activity. Serum ADA concentrations were measured and compared between groups. Overall, 89 patients were included. A total of 27 patients had clinically active CD and 62 were in clinical remission. Forty patients had endoscopic disease activity and 49 were in endoscopic remission. The mean serum ADA concentration was 10.2 μg/mL in patients with clinically active CD and 14.3 μg/mL in patients in clinical remission (p = 0.395). The mean serum ADA concentration in patients with endoscopic activity was 11.3 μg/mL as compared to 14.5 μg/mL in those with endoscopic remission (p = 0.566). There was no difference between serum ADA concentrations regarding clinical or endoscopic activity in CD, as compared to patients in remission Full article

(This article belongs to the Special Issue Recent Advances in Therapeutic Antibody)

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16 pages, 4003 KiB

Open AccessArticle

An Engineered IFNγ-Antibody Fusion Protein with Improved Tumor-Homing Properties

by Cesare Di Nitto, Ettore Gilardoni, Jacqueline Mock, Lisa Nadal, Tobias Weiss, Michael Weller, Frauke Seehusen, Chiara Libbra, Emanuele Puca, Dario Neri and Roberto De Luca

Pharmaceutics 2023, 15(2), 377; https://doi.org/10.3390/pharmaceutics15020377 - 22 Jan 2023

Cited by 1 | Viewed by 2004

Abstract

Interferon-gamma (IFNγ) is one of the central cytokines produced by the innate and adaptive immune systems. IFNγ directly favors tumor growth control by enhancing the immunogenicity of tumor cells, induces IP-10 secretion facilitating (CXCR3+) immune cell infiltration, and can prime macrophages to an [...] Read more.

Interferon-gamma (IFNγ) is one of the central cytokines produced by the innate and adaptive immune systems. IFNγ directly favors tumor growth control by enhancing the immunogenicity of tumor cells, induces IP-10 secretion facilitating (CXCR3+) immune cell infiltration, and can prime macrophages to an M1-like phenotype inducing proinflammatory cytokine release. We had previously reported that the targeted delivery of IFNγ to neoplastic lesions may be limited by the trapping of IFNγ-based products by cognate receptors found in different organs. Here we describe a novel fusion protein consisting of the L19 antibody, specific to the alternatively spliced extra-domain B of fibronectin (EDB), fused to a variant of IFNγ with reduced affinity to its cognate receptor. The product (named L19-IFNγ KRG) selectively localized to tumors in mice, showed favorable pharmacokinetic profiles in monkeys and regained biological activity upon antigen binding. The fusion protein was investigated in two murine models of cancer, both as monotherapy and in combination with therapeutic modalities which are frequently used for cancer therapy. L19-IFNγ KRG induced tumor growth retardation and increased the intratumoral concentration of T cells and NK cells in combination with anti-PD-1. Full article

(This article belongs to the Special Issue Recent Advances in Therapeutic Antibody)

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14 pages, 2248 KiB

Open AccessArticle

Antitumor Activity of an Anti-EGFR/HER2 Bispecific Antibody in a Mouse Xenograft Model of Canine Osteosarcoma

by Nami Tateyama, Hiroyuki Suzuki, Tomokazu Ohishi, Teizo Asano, Tomohiro Tanaka, Takuya Mizuno, Takeo Yoshikawa, Manabu Kawada, Mika K. Kaneko and Yukinari Kato

Pharmaceutics 2022, 14(11), 2494; https://doi.org/10.3390/pharmaceutics14112494 - 17 Nov 2022

Cited by 2 | Viewed by 1866

Abstract

The overexpression of epidermal growth factor receptors (EGFRs) has been reported in various human tumors, including breast, gastric, lung, colorectal, and pancreatic cancers. Humanized anti-EGFR and anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibodies (mAbs) have been shown to improve patients’ survival. [...] Read more.

The overexpression of epidermal growth factor receptors (EGFRs) has been reported in various human tumors, including breast, gastric, lung, colorectal, and pancreatic cancers. Humanized anti-EGFR and anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibodies (mAbs) have been shown to improve patients’ survival. Canine tumors resemble human tumors in the initiation and progression. We previously established a defucosylated mouse-dog chimeric anti-EGFR mAb (E134Bf) and a mouse-dog chimeric anti-HER2 mAb (H77Bf), which exerted antitumor activities in canine tumor xenograft models. Here, we produced E134Bf antibody fused to H77Bf single chain Fv at the light chains (E134Bf-H77scFv). The bispecific E134Bf-H77scFv recognized dog EGFR (dEGFR) and dog HER2 (dHER2)-overexpressed Chinese hamster ovary-K1 cells by flow cytometry. E134Bf-H77scFv also reacted with dEGFR/dHER2-positive canine osteosarcoma D-17 cells, and possesses a high binding-affinity (K_D: 1.3 × 10⁻⁹ M). Furthermore, E134Bf-H77scFv exerted antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against D-17 cells in the presence of canine mononuclear cells and complement, respectively. Moreover, administration of E134Bf-H77scFv suppressed the development of D-17 xenograft tumor in mice early compared with the control dog IgG, E134Bf and H77Bf alone. These results indicate that E134Bf-H77scFv exerts antitumor activities against dEGFR/dHER2-positive canine tumors, and could be a valuable treatment regimen for canine tumors. Full article

(This article belongs to the Special Issue Recent Advances in Therapeutic Antibody)

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Review

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24 pages, 1792 KiB

Open AccessEditor’s ChoiceReview

Fc-Engineered Therapeutic Antibodies: Recent Advances and Future Directions

by Dalia T. Abdeldaim and Katharina Schindowski

Pharmaceutics 2023, 15(10), 2402; https://doi.org/10.3390/pharmaceutics15102402 - 28 Sep 2023

Cited by 4 | Viewed by 3522

Abstract

Monoclonal therapeutic antibodies have revolutionized the treatment of cancer and other diseases. Fc engineering aims to enhance the effector functions or half-life of therapeutic antibodies by modifying their Fc regions. Recent advances in the Fc engineering of modern therapeutic antibodies can be considered [...] Read more.

Monoclonal therapeutic antibodies have revolutionized the treatment of cancer and other diseases. Fc engineering aims to enhance the effector functions or half-life of therapeutic antibodies by modifying their Fc regions. Recent advances in the Fc engineering of modern therapeutic antibodies can be considered the next generation of antibody therapy. Various strategies are employed, including altering glycosylation patterns via glycoengineering and introducing mutations to the Fc region, thereby enhancing Fc receptor or complement interactions. Further, Fc engineering strategies enable the generation of bispecific IgG-based heterodimeric antibodies. As Fc engineering techniques continue to evolve, an expanding portfolio of Fc-engineered antibodies is advancing through clinical development, with several already approved for medical use. Despite the plethora of Fc-based mutations that have been analyzed in in vitro and in vivo models, we focus here in this review on the relevant Fc engineering strategies of approved therapeutic antibodies to finetune effector functions, to modify half-life and to stabilize asymmetric bispecific IgGs. Full article

(This article belongs to the Special Issue Recent Advances in Therapeutic Antibody)

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27 pages, 5036 KiB

Open AccessReview

Advances in Antibody-Based Therapeutics for Cerebral Ischemia

by Jui-Ming Sun, Ting-Lin Yen, Jing-Shiun Jan, Pharaoh Fellow Mwale, Ruei-Dun Teng, Rajeev Taliyan, Cheng-Ta Hsieh and Chih-Hao Yang

Pharmaceutics 2023, 15(1), 145; https://doi.org/10.3390/pharmaceutics15010145 - 31 Dec 2022

Cited by 1 | Viewed by 2330

Abstract

Cerebral ischemia is an acute disorder characterized by an abrupt reduction in blood flow that results in immediate deprivation of both glucose and oxygen. The main types of cerebral ischemia are ischemic and hemorrhagic stroke. When a stroke occurs, several signaling pathways are [...] Read more.

Cerebral ischemia is an acute disorder characterized by an abrupt reduction in blood flow that results in immediate deprivation of both glucose and oxygen. The main types of cerebral ischemia are ischemic and hemorrhagic stroke. When a stroke occurs, several signaling pathways are activated, comprising necrosis, apoptosis, and autophagy as well as glial activation and white matter injury, which leads to neuronal cell death. Current treatments for strokes include challenging mechanical thrombectomy or tissue plasminogen activator, which increase the danger of cerebral bleeding, brain edema, and cerebral damage, limiting their usage in clinical settings. Monoclonal antibody therapy has proven to be effective and safe in the treatment of a variety of neurological disorders. In contrast, the evidence for stroke therapy is minimal. Recently, Clone MTS510 antibody targeting toll-like receptor-4 (TLR4) protein, ASC06-IgG1 antibody targeting acid sensing ion channel-1a (ASIC1a) protein, Anti-GluN1 antibodies targeting N-methyl-D-aspartate (NMDA) receptor associated calcium influx, GSK249320 antibody targeting myelin-associated glycoprotein (MAG), anti-High Mobility Group Box-1 antibody targeting high mobility group box-1 (HMGB1) are currently under clinical trials for cerebral ischemia treatment. In this article, we review the current antibody-based pharmaceuticals for neurological diseases, the use of antibody drugs in stroke, strategies to improve the efficacy of antibody therapeutics in cerebral ischemia, and the recent advancement of antibody drugs in clinical practice. Overall, we highlight the need of enhancing blood–brain barrier (BBB) penetration for the improvement of antibody-based therapeutics in the brain, which could greatly enhance the antibody medications for cerebral ischemia in clinical practice. Full article

(This article belongs to the Special Issue Recent Advances in Therapeutic Antibody)

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