In the past decade, oral inhalation has been a thriving focus of research to administer antibody directly to the lungs as an aerosol, for local treatment of respiratory diseases. Formulation of inhaled antibodies is central for the stability of antibody, lung safety and to ensure inhaler performances. Surfactants have already been shown to prevent antibody degradation during aerosolization, but little is known about the impact of other components of liquid formulations on the structural stability of antibodies. Here, we report for the first time to the best of our knowledge, a significant effect of the buffering system on monoclonal antibodies stability, during mesh-nebulization. While the monoclonal antibody extensively aggregated in citrate buffer after nebulization and required high concentration of polysorbate 80 (PS80) to maintain protein integrity, acetate and histidine buffers resulted in a slight to moderate aggregation without PS80 and low concentration of PS80 was sufficient to stabilize antibody during mesh-nebulization.

01 Oct 2021·Analytica Chimica ActaQ2 · CHEMISTRY

Native fluorescence detection with a laser driven light source for protein analysis in capillary electrophoresis

Q2 · CHEMISTRY

Article

Author: Lies, Mark ; Silzel, John ; Zhu, Zaifang

While ultraviolet light (UV) absorbance detection is the most widely used detection mode in capillary electrophoresis (CE), it can yield poor concentration sensitivity and has tendencies to exhibit baseline fluctuations. In order to overcome these challenges, alternative detection strategies, including the use of dedicated wavelength lasers, have been applied, resulting in enhancements of concentration sensitivity as well as decreased baseline disturbance. In this work, using a laser driven light source for excitation, we reported a native fluorescence detection (NFD) scheme for use in a commercial CE platform, PA 800 Plus Pharmaceutical Analysis System, for protein analysis. The CE-NFD system was characterized using tryptophan and a reduced IgG. We compared NFD with UV absorbance detection as applied to sodium dodecyl sulfate-capillary gel electrophoresis (SDS-CGE) and capillary isoelectric focusing (cIEF). In SDS-CGE, with the reported NFD a non-reduced IgG standard sample yielded a signal-to-noise ratio which was 14.6 times higher than with UV absorbance detection at 214 nm. In cIEF analysis of NISTmAb, Humanized IgG1_k, with NFD ∼170 times less sample mass was needed to obtain similar profile quality to that with UV absorbance detection at 280 nm. NFD also eliminated baseline anomalies observed with UV absorbance detection and showed less interference by other absorbing species. These results suggest that CE-NFD is a practical and powerful tool for protein characterization in the biopharmaceutical industry.

01 Jan 2021·Computational and Structural Biotechnology JournalQ3 · BIOLOGY

In silico antibody engineering for SARS-CoV-2 detection

Q3 · BIOLOGY

ArticleOA

Author: Martín-Martínez, Eduard ; Turon, Pau ; Martí, Didac ; Bertran, Oscar ; Alemán, Carlos ; Torras, Juan

Engineered immunoglobulin-G molecules (IgGs) are of wide interest for the development of detection elements in protein-based biosensors with clinical applications. The strategy usually employed for the de novo design of such engineered IgGs consists on merging fragments of the three-dimensional structure of a native IgG, which is immobilized on the biosensor surface, and of an antibody with an exquisite target specificity and affinity. In this work conventional and accelerated classical molecular dynamics (cMD and aMD, respectively) simulations have been used to propose two IgG-like antibodies for COVID-19 detection. More specifically, the crystal structure of the IgG1 B12 antibody, which inactivates the human immunodeficiency virus-1, has been merged with the structure of the antibody CR3022 Fab tightly bounded to SARS-CoV-2 receptor-binding domain (RBD) and the structure of the S309 antibody Fab fragment complexed with SARS-CoV-2 RBD. The two constructed antibodies, named IgG1-CR3022 and IgG1-S309, respectively, have been immobilized on a stable gold surface through a linker. Analyses of the influence of both the merging strategy and the substrate on the stability of the two constructs indicate that the IgG1-S309 antibody better preserves the neutralizing structure than the IgG1-CR3022 one. Overall, results indicate that the IgG1-S309 is appropriated for the generation of antibody based sensors for COVID-19 diagnosis.

News (Medical) associated with M4-3-ML2

21 Feb 2024

·www.businesswire.com

Immune-Onc Therapeutics Announces Orphan Drug Designation Granted by US FDA for IO-202 (Anti-LILRB4) for the Treatment of Chronic Myelomonocytic Leukemia (CMML)

PALO ALTO, Calif.--( BUSINESS WIRE )--Immune-Onc Therapeutics, Inc. (“Immune-Onc”), a clinical-stage biopharmaceutical company advancing novel therapies in immunology and oncology by targeting myeloid cell inhibitory receptors, today announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation for IO-202 for the treatment of chronic myelomonocytic leukemia (CMML). IO-202 received Fast Track Designation for treatment of relapsed or refractory CMML in 2023. In addition, Fast Track and Orphan Drug Designations for IO-202 were granted by the FDA for the treatment of acute myeloid leukemia (AML) in 2022 and 2020, respectively. IO-202 is a first-in-class antagonist antibody with specific, high affinity binding to Leukocyte Immunoglobulin-Like Receptor subfamily B4 (LILRB4) and serves as a targeted therapy with broad potential in blood cancers, autoimmune and inflammatory diseases. IO-202 in combination with azacitidine (AZA) is currently in a Phase 1 dose expansion clinical trial ( NCT04372433 ), enrolling newly diagnosed patients with CMML who have not received any hypomethylating agents (HMA). A dose escalation trial of IO-202 has been completed, showing clinical efficacy in relapsed or refractory AML and CMML, either as a monotherapy or in combination with AZA. IO-202 has been shown to be well tolerated in all patients treated to date. “Although current therapeutic options for CMML can improve a patient’s quality of life, there is a high unmet need for effective disease-modifying approaches that are potentially curative,” said Charlene Liao Ph.D., chief executive officer and board chair of Immune-Onc. “We are very proud that the FDA has granted IO-202 Orphan Drug Designation for the treatment of CMML. We look forward to continued collaborations with our investigators and the FDA as we work to bring this potentially important therapy to patients with hard-to-treat blood cancers.” The FDA grants Orphan Drug Designation to medicines and potential new medicines intended for the treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the U.S. Orphan Drug Designation qualifies the sponsor for various development incentives of the Orphan Drug Act, including exemption of FDA application fees and tax credits for qualified clinical testing, and conveys seven years of marketing exclusivity for a drug approved to treat an orphan disease in the United States. ABOUT CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) CMML is a rare form of blood cancer, occurring in 4 of every 1,000,000 people in the United States each year, or about 1,100 annual cases 1 . CMML is characterized by the presence of a high monocyte count (>1x10 9 /L peripheral monocytes with monocytes ≥ 10% of white blood count) along with dysplastic features in the bone marrow 2 . Current FDA approved therapies for CMML are all hypomethylating agents, including azacitidine, that attempt to control CMML without enhancement to overall survival. ABOUT LILRB4 (also known as ILT3) LILRB4, also known as ILT3, is an immune-modulatory transmembrane protein found on monocytes and monocyte-derived cells. LILRB4 is expressed on certain hematologic cancer cells, such as myelomonocytic leukemia blasts, and on certain pathogenic cells involved in autoimmunity and inflammatory processes. About IO-202 IO-202 is a first-in-class antagonist antibody with specific, high affinity binding to LILRB4. IO-202 is a humanized IgG1 antibody with Fc effector function to kill LILRB4 hi cells via antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). As such, IO-202 is a targeted therapy with broad potential in both blood cancers and autoimmune and inflammatory diseases. IO-202 has completed the dose escalation part of the first-in-human, multicenter, open-label Phase 1 study in the U.S., and the data was presented at the European Hematology Association (EHA) Congress in 2023. This Phase 1 trial has advanced to the dose expansion stage to evaluate IO-202 in combination with azacitidine ( NCT04372433 ) in patients with newly diagnosed chronic myelomonocytic leukemia (CMML) who have not received any hypomethylating agents (HMA). The U.S. Food and Drug Administration granted IO-202 Fast Track Designations for treatment for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) and for the treatment of patients with relapsed or refractory chronic myelomonocytic leukemia (CMML). The FDA has also granted Orphan Drug Designations to IO-202 for the treatment of AML and for the treatment of CMML. ABOUT IMMUNE-ONC THERAPEUTICS, INC. Immune-Onc Therapeutics Inc. (“Immune-Onc”) is a private, clinical-stage biopharmaceutical company developing novel therapies in immunology and oncology by targeting myeloid cell inhibitory receptors. Immune-Onc has a differentiated pipeline with a current focus on targeting the Leukocyte Immunoglobulin-Like Receptor subfamily B (LILRB). Immune-Onc’s focused platform approach has led to the development of several promising therapeutics across various stages of development. Those include IO-108, an antagonist antibody targeting LILRB2 (also known as ILT4), in Phase 1b/2 clinical development for solid tumors, and IO-202, a first-in-class antagonist antibody targeting LILRB4 (also known as ILT3), in Phase 1b clinical development for the treatment of acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML). IO-202 has the potential to be the best-in-class antibody therapy for lupus and can extend to other indications in immunology and inflammation. Additional assets in Immune-Onc’s pipeline include IO-312 (a novel bispecific antibody targeting LILRB4 and CD3), IO-106 (first-in-class antagonist antibody targeting LAIR1), and undisclosed immunology and oncology programs. Immune-Onc has established agreements with leading biopharmaceutical companies, including BeiGene , Regeneron and Roche , to support its global product development plans for IO-108 and IO-202. It has received research grants from the National Cancer Institute (NCI) of the National Institutes of Health (NIH) and the California Institute for Regenerative Medicine (CIRM) and investment from The Leukemia & Lymphoma Society Therapy Acceleration Program® (LLS TAP®). Headquartered in Palo Alto, California, Immune-Onc has assembled a diverse team with deep expertise in drug development and proven track records of success at leading biopharmaceutical companies. For more information, please visit www.immune-onc.com and follow us on X and LinkedIn . Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood. 2008 Jul 1;112(1):45-52. doi: 10.1182/blood-2008-01-134858 Chronic myelomonocytic leukemia: 2022 update on diagnosis, risk stratification, and management. Am J Hematol. 2022 Mar 1;97(3):352-372. doi: 10.1002/ajh.26455.

Orphan DrugFast TrackPhase 1Immunotherapy

13 Oct 2023

·www.prnewswire.com

Inmagene Doses First Patient in Phase 2a Trial of IMG-007, an Anti-OX40 Monoclonal Antibody with an Extended Half-life, for the Treatment of Alopecia Areata

IMG-007 is a novel anti-OX40 monoclonal antibody (mAb) engineered for potentially once every 12 weeks dosing and an improved safety profile IMG-007 is being evaluated for the treatment of alopecia areata (AA) and atopic dermatitis (AD) An interim data readout in AA is expected in Q3 2024 SAN DIEGO, Oct. 13, 2023 /PRNewswire/ -- Inmagene Biopharmaceuticals ("Inmagene"), a clinical stage biotechnology company developing innovative and differentiated therapies for immunological and inflammatory diseases, announced that the first patient has been dosed in a global multicenter Phase 2a study of IMG-007 in adult patients with AA. The study will evaluate the safety, efficacy, pharmacokinetics, and biomarkers of IMG-007 in AA patients with 50% or greater scalp hair loss. More information about the study can be found here NCT06060977. "Alopecia areata is a devastating disease which affects approximately 147 million people globally. Currently, there are limited treatment options and no approved biologics for AA. Better treatment options are needed," said Jonathan Wang, Ph.D., Chief Executive Officer of Inmagene. "IMG-007 could potentially provide a safe and effective biologic therapy with once every 12 weeks dosing regimen for AA patients." IMG-007 is a humanized IgG1 mAb that specifically binds to the OX40 receptor and potently blocks the signaling between OX40 and its ligand. IMG-007 has been engineered to have an extended half-life to allow less frequent dosing and a silenced antibody-dependent cell-mediated cytotoxicity (ADCC) function to reduce safety risks. In a Phase 1 study in healthy adult participants, IMG-007 has demonstrated a favorable safety profile, without any reports of pyrexia or chills. A single treatment of IMG-007 at projected therapeutic dose levels maintained the target exposure for 12 to 18 weeks, which may allow IMG-007 for every 12 weeks administration. In addition to the global Phase 2a study in AA patients, IMG-007 is also being evaluated in a global Phase 2a study in adult patients with AD with an interim data readout expected in Q2 2024. About Inmagene Inmagene is a global clinical-stage biotechnology company focused on developing novel therapeutics for immunological and inflammatory diseases. It has four clinical-stage drug candidates. The lead compound, IMG-007, an OX40 antagonist mAb with an extended half-life and a silenced ADCC function, is in two global Phase 2a clinical trials. IMG-004, a non-covalent, reversible BTK inhibitor, which has demonstrated a more durable pharmacodynamic effect and longer half-life than most leading BTK inhibitors, is completing Phase 1 clinical development. IMG-008, a long-acting anti-IL-36R mAb with a longer half-life and higher exposure than an approved IL-36R antagonist, is entering global Phase 1 clinical development. Moreover, IMG-020 (izokibep), an anti-IL-17 small protein therapeutic, is in global clinical development for 5 indications, including 2 pivotal trials, in collaboration with global partners. Based on its proprietary QuadraTek® platform, Inmagene discovers and develops novel drug candidates. Inmagene has out-licensed IMG-018, a differentiated anti-ILT7 mAb drug candidate, to establish a new drug development company Celexor Bio, in collaboration with Aditum Bio. Inmagene has formed strategic partnerships with multiple partners, such as HUTCHMED and Affibody AB, to develop highly innovative drug candidates. About IMG-007 IMG-007 is a humanized IgG1 mAb specifically binds to OX40, a co-stimulatory receptor that is present primarily on activated T cells. OX40-OX40L axis is important in T cell activation, expansion, and survival, thereby having an important role in the pathogenesis of a spectrum of immunological and inflammatory diseases. In nonclinical studies, IMG-007 potently blocks the signaling between OX40 and OX40L. IMG-007 was discovered by HUTCHMED, with Inmagene assuming global development responsibility at the candidate stage. Inmagene owns global rights for IMG-007. About Alopecia Areata Alopecia areata is a chronic autoimmune disease characterized by nonscarring hair loss involving the scalp, face, and/or body. It can affect people of all ages. Approximately 2% of the general population can be affected by AA during their lifetime1,2. Approximately 43% of AA patients have over 50% hair loss3. AA significantly impacts patients' daily life and often leads to profound psychological distress, social isolation, anxiety, and depression. The immunopathogenesis of AA and AD largely overlaps, and AA and AD coexist in many patients4,5. Forward-Looking Statements This press release contains forward-looking statements. While Inmagene believes the projections to be based on reasonable assumptions, these forward-looking statements may be called into question by a number of hazards and uncertainties, so that actual results may differ materially from those anticipated in such forward-looking statements. Media For inquiries, please contact: Anna Vardanyan public.relations@inmagenebio.com SOURCE Inmagene

Phase 2Phase 1Immunotherapy

18 Aug 2023

·www.prnewswire.com

Inmagene's anti-OX40 mAb demonstrated an extended half-life and a favorable safety profile in a Phase I study

IMG-007 has the potential to provide Q12W or less frequent dosing based on an extended half-life IMG-007 has demonstrated a favorable safety profile, consistent with a silenced ADCC function via bioengineering IMG-007 is being evaluated in two global proof-of-concept trials SAN DIEGO, Aug. 18, 2023 /PRNewswire/ -- Inmagene Biopharmaceuticals ("Inmagene"), a clinical stage biotechnology company developing innovative and differentiated therapies for immunological and inflammatory diseases, announced topline results from a Phase 1 study of IMG-007, an anti-OX40 monoclonal antibody (mAb). The key objective of this randomized, double-blind, placebo-controlled, single ascending dose study was to assess the safety and pharmacokinetics of IMG-007 in healthy adults. A total of 30 participants received IMG-007, up to 600 mg, and 14 received placebo. Participants were followed up for up to 18 weeks. IMG-007 is a humanized IgG1 mAb that specially binds to the OX40 receptor with high affinity. It has been engineered in the Fc region to silence the antibody-dependent cell-mediated cytotoxicity (ADCC) function to minimize potential safety risks. In this Phase 1 study, IMG-007 demonstrated a favorable safety profile, with no notable adverse events occurring more frequently in IMG-007 than the placebo group, except for isolated COVID-19 cases with no dose-related trend. No participants reported any treatment-related adverse events. Importantly, there were no reports of pyrexia or chills. The overall favorable safety profile is consistent with a silenced ADCC function. At projected therapeutic dose levels, IMG-007 demonstrated a mean terminal half-life of 31 days, longer than the average half-life of typical IgG mAbs. A single treatment of IMG-007 at projected therapeutic dose levels maintained the target exposure for 12 to 18 weeks, which would allow IMG-007 to be potentially administered every 12 weeks or less frequently. "IMG-007 is significantly different from other OX40/OX40L drug candidates due to its extended half-life and silenced ADCC function," said Jonathan Wang, PhD, Chief Executive Officer of Inmagene. "IMG-007's potential to provide patients with long 'drug holidays', combined with a favorable safety profile, supports its best-in-class potential as an OX40 targeted therapy." A global proof-of-concept (POC) trial of IMG-007 in adult patients with moderate-to-severe atopic dermatitis is actively enrolling patients. Another POC trial in a first-in-class indication has also been initiated. About Inmagene Inmagene is a global clinical-stage biotechnology company focused on developing novel therapeutics for immunological and inflammatory diseases. It has four clinical-stage drug candidates. The lead compound, IMG-007, an OX40 antagonist mAb with an extended half-life and a silenced ADCC function, is in two global POC clinical trials. IMG-004, a non-covalent, reversible Bruton's tyrosine kinase (BTK) inhibitor, which has demonstrated more durable pharmacodynamic effect and longer half-life than any of the leading BTK inhibitors, is completing Phase 1 clinical development. IMG-008, a long-acting mAb against IL-36R with an extended half-life and enhanced antibody exposure compared to an approved IL-36R antagonist, is entering global Phase 1 clinical development. Moreover, IMG-020 (izokibep), an anti-IL-17 small protein therapeutic, is in global clinical development for 5 indications, including 2 pivotal trials, in collaboration with global partners. Based on its proprietary QuadraTek® platform, Inmagene discovers and develops novel drug candidates. Inmagene also sources innovation via in-licensing activities and, together with its partners, carries out global development activities. Inmagene has formed strategic partnerships with multiple partners, such as HUTCHMED and Affibody AB, to develop highly innovative drug candidates. About IMG-007 IMG-007 is a humanized IgG1 mAb specifically binds to OX40, a co-stimulatory receptor that is present primarily on activated T cells. OX40-OX40L axis is important in T cell activation, expansion, and survival, thereby having an important role in the pathogenesis of a spectrum of immunological and inflammatory diseases. In nonclinical studies, IMG-007 potently and completely blocks signaling between OX40 and OX40L. IMG-007 was discovered by HUTCHMED, with Inmagene assuming global development responsibility at the candidate stage. Inmagene owns an exclusive option for IMG-007's global rights. Forward-Looking Statements This press release contains forward-looking statements. While Inmagene believes the projections to be based on reasonable assumptions, these forward-looking statements may be called into question by a number of hazards and uncertainties, so that actual results may differ materially from those anticipated in such forward-looking statements. SOURCE Inmagene

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Neoplasms	Preclinical	-	Roche Holding AG	-

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