eflepedocokin alfa (F-652) / Yifan Pharma - LARVOL DELTA

Use of a Tissue-Targeting Recombinant Human Interleukin-22 Fusion Molecule (F-652) for the Treatment of Advanced Refractory Lower GI Acute Gvhd (ASH 2023) - " Three patients with hematologic malignancies underwent MUD allo-HCT with tacrolimus and methotrexate GVHD prophylaxis ( Table)...These CRP elevations occurred despite concurrent use of belumosidil in Patient A and ruxolitinib in Patient C. CRP levels increased in Patient B after the first two doses, but not the third ( Figure)... This is the first report of IL-22 therapy in SR aGVHD. Treatment was well tolerated, and 2-of-3 patients achieved a response following rhIL-22 administration after failing multiple previous therapies. Whereas most treatments for GVHD target immune cells and deepen immunosuppression, IL-22 is understood to act directly upon epithelial cells where it can support tissue recovery, improve barrier function, and promote innate antimicrobial immunity."

Metastases • Acute Graft versus Host Disease • Gastrointestinal Disorder • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Oncology • Transplantation • CRP • IL10 • IL22

Study of F-652 in Subjects With Corona Virus Disease 2019 (COVID-19) Pneumonia (clinicaltrials.gov) - P2a | N=0 | Withdrawn | Sponsor: EVIVE Biotechnology | N=60 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Infectious Disease • Novel Coronavirus Disease • Pneumonia

A phase 2 study of Interleukin-22 and systemic corticosteroids as initial treatment for acute GVHD of the lower GI tract. (PubMed, Blood) - P2a | "We conducted a multicenter single-arm phase 2 study evaluating safety and efficacy of a novel recombinant human Interleukin-22 dimer, F-652, used in combination with systemic corticosteroids for treatment of newly diagnosed lower gastrointestinal acute GVHD (NCT02406651; https://clinicaltrials.gov/ct2/show/NCT02406651)...This work demonstrates a potential approach for combining immunosuppression with tissue-supportive strategies to enhance recovery of damaged mucosa and promote microbial health in patients with gastrointestinal GVHD. This work was supported by funding from Evive Biotech., The Society of Memorial Sloan Kettering Cancer Center, and the National Institutes of Health."

Journal • P2 data • Acute Graft versus Host Disease • Gastrointestinal Disorder • Graft versus Host Disease • Hematological Disorders • Immunology • Oncology • Transplantation • IL22

Study of IL-22 IgG2-Fc (F-652) for Subjects With Grade II-IV Lower GI aGVHD (clinicaltrials.gov) - P2a; N=30; Completed; Sponsor: Generon (Shanghai) Corporation Ltd.; Active, not recruiting ➔ Completed

Trial completion • Bone Marrow Transplantation • Gastrointestinal Disorder • Graft versus Host Disease • Immunology • Transplantation

Interleukin-22 protects from endotoxemia by inducing suppressive F4/80Ly6GLy6C cells population. (PubMed, BMC Immunol) - "Our study suggests that IL-22 has a protective role against endotoxemia by inducing the development of immunosuppressive cells through S100A9."

Journal • Infectious Disease • Inflammation • IL1B • IL22 • IL6 • S100A9 • TNFA

Study of F-652 (IL-22:IgG2 Fusion Protein) in Patients With Moderate to Severe COVID-19 (clinicaltrials.gov) - P2 | N=1 | Terminated | Sponsor: EVIVE Biotechnology | N=38 ➔ 1 | Trial completion date: Dec 2021 ➔ Mar 2021 | Recruiting ➔ Terminated | Trial primary completion date: Dec 2021 ➔ Mar 2021; There have been significant changes in the FDA guidelines and clinical standard of care

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Infectious Disease • Novel Coronavirus Disease

Study of F-652 in Subjects With Corona Virus Disease 2019 (COVID-19) Pneumonia (clinicaltrials.gov) - P2a; N=60; Not yet recruiting; Sponsor: EVIVE Biotechnology

New P2a trial • Infectious Disease • Novel Coronavirus Disease • Pneumonia • PCR

Study of F-652 (IL-22:IgG2 Fusion Protein) in Patients With Moderate to Severe COVID-19 (clinicaltrials.gov) - P2; N=38; Recruiting; Sponsor: Generon (Shanghai) Corporation Ltd.; Trial primary completion date: Sep 2021 ➔ Dec 2021

Clinical • Trial primary completion date • Infectious Disease • Novel Coronavirus Disease

[VIRTUAL] Cellular Internalization and Localization of Once-Weekly Basal Insulin Fc (BIF) (ADA 2021) - "BIF is comprised of a human single-chain insulin fused to a human IgG2 Fc domain through a peptide linker. The subcellular trafficking pattern of BIF is similar to human insulin. BIF undergoes rapid internalization and transport to early endosomes with limited transport to the lysosomes and undergoes loss of cellular immunostaining during ligand washout."

Diabetes • Metabolic Disorders • IR • LAMP1

[VIRTUAL] A PHASE 2 STUDY OF F-652, A NOVEL TISSUE-TARGETED RECOMBINANT HUMAN INTERLEUKIN-22 (IL-22) DIMER, FOR TREATMENT OF NEWLY DIAGNOSED ACUTE LOWER GI GVHD (EBMT 2020) - P2a | "IL-22 in combination with corticosteroids was well tolerated and the 70% lower GI aGVHD response rate met the primary efficacy endpoint. These findings support further development of this approach and provide a proof-of-concept for combining standard immunosuppression with tissue-supportive strategies to enhance recovery of damaged mucosa, promote microbial health, and improve GVHD treatment response. Furthermore, our findings suggest that monitoring of the intestinal microbiome could function as a biomarker of treatment response in GI aGVHD."

P2 data • Gastrointestinal Disorder • Graft versus Host Disease • Immunology • Infectious Disease • Musculoskeletal Diseases • Pneumonia • Respiratory Diseases • Septic Shock • Sinusitis

[VIRTUAL] A PHASE 2 STUDY OF F-652, A NOVEL TISSUE-TARGETED RECOMBINANT HUMAN INTERLEUKIN-22 (IL-22) DIMER, FOR TREATMENT OF NEWLY DIAGNOSED ACUTE LOWER GI GVHD (EBMT 2020) - P2a | "IL-22 in combination with corticosteroids was well tolerated and the 70% lower GI aGVHD response rate met the primary efficacy endpoint. These findings support further development of this approach and provide a proof-of-concept for combining standard immunosuppression with tissue-supportive strategies to enhance recovery of damaged mucosa, promote microbial health, and improve GVHD treatment response. Furthermore, our findings suggest that monitoring of the intestinal microbiome could function as a biomarker of treatment response in GI aGVHD."

P2 data • Gastrointestinal Disorder • Graft versus Host Disease • Immunology • Infectious Disease • Musculoskeletal Diseases • Pneumonia • Respiratory Diseases • Septic Shock • Sinusitis

[VIRTUAL] Preclinical Characterization of Once Weekly Basal Insulin Fc (BIF) (ENDO 2021) - "BIF is comprised of a human single-chain insulin fused to a human IgG2 Fc domain through a peptide linker. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO 2021."

Preclinical • Diabetes • Metabolic Disorders • Type 1 Diabetes Mellitus • Type 2 Diabetes Mellitus • IR

Study of F-652 (IL-22:IgG2 Fusion Protein) in Patients With Moderate to Severe COVID-19 (clinicaltrials.gov) - P2; N=38; Recruiting; Sponsor: Generon (Shanghai) Corporation Ltd.; Trial completion date: Jun 2021 ➔ Dec 2021; Trial primary completion date: May 2021 ➔ Sep 2021

Clinical • Trial completion date • Trial primary completion date • Infectious Disease • Novel Coronavirus Disease

[VIRTUAL] A PHASE 2 STUDY OF F-652, A NOVEL TISSUE-TARGETED RECOMBINANT HUMAN INTERLEUKIN-22 (IL-22) DIMER, FOR TREATMENT OF NEWLY DIAGNOSED ACUTE LOWER GI GVHD (EBMT 2020) - P2a | "IL-22 in combination with corticosteroids was well tolerated and the 70% lower GI aGVHD response rate met the primary efficacy endpoint. These findings support further development of this approach and provide a proof-of-concept for combining standard immunosuppression with tissue-supportive strategies to enhance recovery of damaged mucosa, promote microbial health, and improve GVHD treatment response. Furthermore, our findings suggest that monitoring of the intestinal microbiome could function as a biomarker of treatment response in GI aGVHD."

P2 data • Gastrointestinal Disorder • Graft versus Host Disease • Immunology • Infectious Disease • Musculoskeletal Diseases • Pneumonia • Respiratory Diseases • Septic Shock • Sinusitis

[VIRTUAL] A PHASE 2 STUDY OF F-652, A NOVEL TISSUE-TARGETED RECOMBINANT HUMAN INTERLEUKIN-22 (IL-22) DIMER, FOR TREATMENT OF NEWLY DIAGNOSED ACUTE LOWER GI GVHD (EBMT 2020) - P2a | "IL-22 in combination with corticosteroids was well tolerated and the 70% lower GI aGVHD response rate met the primary efficacy endpoint. These findings support further development of this approach and provide a proof-of-concept for combining standard immunosuppression with tissue-supportive strategies to enhance recovery of damaged mucosa, promote microbial health, and improve GVHD treatment response. Furthermore, our findings suggest that monitoring of the intestinal microbiome could function as a biomarker of treatment response in GI aGVHD."

P2 data • Gastrointestinal Disorder • Graft versus Host Disease • Immunology • Infectious Disease • Musculoskeletal Diseases • Pneumonia • Respiratory Diseases • Septic Shock • Sinusitis

FcRn, but not FcγRs, drives maternal-fetal transplacental transport of human IgG antibodies. (PubMed, Proc Natl Acad Sci U S A) - "No differences in IgG1 Fc glycan profiles and minimal differences in IgG2 Fc glycans were noted, whereas the presence or absence of galactose on the Fc glycan of IgG1 did not alter FcγRIIIa or FcRn binding, half-life, or their ability to deplete target cells in FcγR/FcRn humanized mice...In contrast, enhancing FcγRIIIa binding did not result in enhanced maternal-fetal transport. These results argue against a role for FcγRs in IgG transplacental transport, suggesting Fc engineering of maternally administered antibody to enhance only FcRn binding as a means to improve maternal-fetal transport of IgG."

Journal

Study of F-652 (IL-22:IgG2 Fusion Protein) in Patients With Moderate to Severe COVID-19 (clinicaltrials.gov) - P2; N=38; Recruiting; Sponsor: Generon (Shanghai) Corporation Ltd.; Not yet recruiting ➔ Recruiting

Enrollment open • Infectious Disease • Novel Coronavirus Disease

Safety, pharmacokinetics, and biomarkers of F-652, a recombinant human interleukin-22 dimer, in healthy subjects. (PubMed, Cell Mol Immunol) - "In conclusion, IV administration of F-652 to healthy male volunteers is safe and well-tolerated and demonstrates favorable PK and pharmacodynamic properties. These results warrant further clinical development of F-652 to treat inflammatory diseases."

Biomarker • Clinical • IO Biomarker • Journal • PK/PD data • Atopic Dermatitis • Dermatitis • Dermatology • Dermatopathology • Immunology

Study of F-652 (IL-22:IgG2 Fusion Protein) in Patients With Moderate to Severe COVID-19 (clinicaltrials.gov) - P2; N=38; Not yet recruiting; Sponsor: Generon (Shanghai) Corporation Ltd.

Clinical • New P2 trial • Infectious Disease • Novel Coronavirus Disease

BARDA, Genentech to accelerate phase 2 clinical trial for two investigational Covid-19 treatments (Homeland Preparedness News) - "A partnership between the Biomedical Advanced Research and Development Authority (BARDA) and biotechnology company Genentech will yield a phase 2 clinical trial to evaluate two investigational drugs for the treatment of severe COVID-19 cases: anti-ST2 and IL-22-Fc. The drugs will be tested on approximately 300 patients with severe COVID-19 pneumonia that has forced them to take supplemental oxygen."

Licensing / partnership • New P2 trial • Infectious Disease • Novel Coronavirus Disease

Fusion of pseudorabies virus glycoproteins to IgG Fc enhances protective immunity against pseudorabies virus. (PubMed, Virology) - "Further, the gB-IgG2aFc subunit vaccine was efficient for PRV infection compared with live attenuated vaccine. Overall, these results suggest that IgG2a Fc fragment, as a potential molecular adjuvant, fused with PRV antigen might be a promising and efficient PRV vaccine candidate."

Journal

A Phase 2 Study of F-652, a Novel Tissue-Targeted Recombinant Human Interleukin-22 (IL-22) Dimer, for Treatment of Newly Diagnosed Acute Gvhd of the Lower GI Tract (TCT-ASTCT-CIBMTR 2020) - "IL-22 in combination with corticosteroids was well tolerated and the 70% lower GI aGVHD response rate met the primary efficacy endpoint. These findings support further development of this approach and provide a proof-of-concept for combining standard immunosuppression with tissue-supportive strategies to enhance recovery of damaged mucosa, promote microbial health, and improve GVHD treatment response."

P2 data

"#TCTM20 Ponce: F652 responders had more microbiome diversity at baseline and after treatment, preserved blautia abundance" (@hemedoc)

"#TCTM20 Ponce: reasonable AE profile with rIL22 F652, most common dry skin. 28d ORR 70%" (@hemedoc)

In vitro elimination of EGFR-overexpressing cancer cells by CD32A chimeric receptor T cells in combination with cetuximab or panitumumab. (PubMed, Int J Cancer) - "The inability of panitumumab to trigger ADCC reflects the poor binding affinity of human IgG2 Fc for the FcγRIII (CD16) on natural killer (NK) cells. The ADCC of Fcγ-CR T cells was associated with the over-expression of EGFR on ECCs. In conclusion, CD32A -CR T cells are efficiently redirected by cetuximab or panitumumab against BC cells overexpressing EGFR."

Combination therapy • Journal • Preclinical