Agonistic Monoclonal Antibody Research Articles

A phase II, multi-center, open-label study to evaluate the safety and efficacy of YH003 in combination with toripalimab (anti-PD-1 mAb) in patients with unresectable/metastatic pancreatic ductal adenocarcinoma (PDAC).

4146 Background: Pancreatic cancer therapy remains a formidable challenge. Although chemotherapy offers tumor control and clinical stabilization, both standard regimens are limited in response durability and incur toxicity. YH003, a humanized agonistic anti-CD40 monoclonal antibody specifically recognizes and agonizes CD40 to enhance immune responses, has demonstrated good safety and promising antitumor activity in Phase I clinical studies in patients with solid tumors. Here, we report the results of the phase II study of YH003 plus Toripalimab with/without chemotherapy, as 1L or 2L treatment in patients with metastatic PDAC. Methods: Patients with unresectable/metastatic (u/m) PDAC were enrolled into two Cohorts. In the second and plus line (2L+) Cohort, patients who had confirmed progressive disease during treatment with first line standard of therapy were enrolled and received 0.3 mg/kg YH003 plus 240 mg Toripalimab, iv, every 21 days. In the 1L Cohort, patients without any prior systemic treatment were enrolled and received 0.3 mg/kg YH003 plus 240 mg Toripalimab plus nab-paclitaxel + gemcitabine, iv, every 21 days. The treatment continued for 12 months if subject was deriving an ongoing clinic benefit. The primary endpoint was overall Response Rate (ORR) by investigator’s assessment per RECIST 1.1. The medium Progression-Free Survival (mPFS) and Overall Survival (mOS) were secondary endpoints. Results: A total of 92 patients were enrolled including 45 subjects for the 2L+ Cohort and 47 subjects for the 1L Cohort. In the 2L+ Cohort, 40 (including 14 Caucasians) of 45 patients had at least 1 evaluable post-treatment tumor assessment, the unconfirmed ORR was observed in 4 patients (10.0%) with 4 partial responses (PR). 10 patients (25.0%) had stable disease (SD), and the Disease Control Rate (DCR) was 35.0%. The mOS was 7.23 months. For the Caucasian subgroup (n = 14), the ORR was 7.1%, DCR was 50%, mPFS was 2.25 months and mOS 9.54 months. For the 1L Cohort, 43 (including 10 Caucasians) of 47 patients had at least 1 evaluable post-treatment tumor assessment, the unconfirmed ORR was observed in 12 patients (27.9%) with 1 CR and 11 PR. 23 patients (53.5%) had SD, and the DCR was 81.4%. The mOS time was 12.12 months. For the Caucasian subgroup (n = 10), the ORR was 50%, DCR was 100%, mPFS was 11.27 months and mOS 19.78 months. The grade 3 or above adverse events that occurred in the 92 patients were 57.8% (26/45) in 2L+ Cohort and 74.5% (35/47) in 1L Cohort. There is no significant safety signal from the study. Conclusions: The results of the phase II study have shown that YH003 plus Toripalimab with/without chemotherapy, as 1L or 2L treatment in patients with u/m PDAC have promising antitumor activity and response durability, especially in the Caucasian subgroups. Both treatment regimens are well tolerated. Clinical trial information: NCT05031494 .

A phase Ib/II study of an anti-CD137 agonist antibody ADG106 in combination with weekly paclitaxel and dose-dense doxorubicin/cyclophosphamide.

e14507 Background: ADG106 is a fully human agonistic anti-CD137 IgG4 monoclonal antibody which modulates the tumor microenvironment and has demonstrated increased efficacy when added to chemotherapy in preclinical models. We studied the combination of ADG106 with chemotherapy. Methods: We conducted a phase Ib trial in patients with advanced solid tumors to determine the recommended phase 2 dose (RP2D) of ADG106 + weekly P (paclitaxel 80mg/m2) or ddAC (doxorubicin 60mg/m2, cyclophosphamide 600mg/m2 Q2W with pegfilgrastim), followed by a phase II trial of neoadjuvant ADG106 + weekly Px12→ADG106 + ddACx4→surgery in stage I-III HER2 negative breast cancer patients. In phase Ib, one dose of single agent ADG106 was administered followed 2 weeks later by ADG106 + ddAC (Cohort 1) or ADG106 + weekly P (Cohort 2). Dose levels (DL) of ADG106 were 50mg (DL-1), 100mg (DL1), 200mg (DL2). Serial tumor biopsies were performed at baseline, after single agent ADG106 and at disease progression in phase I, and at baseline, after single agent ADG106, after cycle 1 ADG106 + P, and at surgery in phase II for translational studies. Results: 11 patients were enrolled into Phase Ib with median 3 (range 2-11) prior lines of palliative systemic therapy. ADG106 + ddAC (n=2 at DL1) was deemed intolerable with 1 patient experiencing G4 neutropenia and the other G3 infection; thus ADG106 was not added to ddAC in phase II. No DLTs were observed in all patients receiving ADG106 + P (n=6 at DL1; n=3 at DL2); ADG106 RP2D was declared at 200mg + P. In this cohort, the most common all-grade AEs were neutropenia (n=6), peripheral neuropathy (n=6) and fatigue (n=6); significant ≥G3 AEs were infection (n=2) and G3 neutropenia (n=6). 5/11 (45%) patients in phase I achieved clinical benefit (CBR; PR=2, SD=3) which is clinically meaningful as 9/11 (82%) had prior taxane exposure. 18 of the planned 30 patients have been enrolled into Phase II (ADG106+weekly P→ddACx4→surgery); 10 have completed study treatment and 5 have undergone surgery. While on ADG106 + P, 4 patients experienced G3 adverse events (AEs): neutropenia (n=3), hypophosphatemia (n=1), fever (n=1). Most common G1-2 AEs were ALT elevation (n=4), acneiform rash (n=3) and peripheral neuropathy (n=3). While on ddAC alone, all AEs were low grade except for 1 patient who had G3 pneumonitis from Pneumocystis Jiroveci Pneumonia. 26 sets of matched tumor biopsies have been collected (9 in phase I; 17 in phase II) and will be tested for a panel of 40 markers by multiplex IHC, including CD137, PD-L1, and CD3/4/8. Conclusions: ADG106 when combined with ddAC exacerbates neutropenia and is not tolerable despite prophylactic pegfilgrastim. The RP2D of ADG106 in combination with P is 200mg and is safe and tolerable; manageable G3 neutropenia was the most common AE. There are no new safety signals thus far in Phase II. Further efficacy analyses and studies on tumor immune markers are ongoing. Clinical trial information: NCT05275777 .

Abstract PO1-19-08: Phase I trial of pegylated liposomal doxorubicin chemotherapy in combination with CD40 agonist and Flt3 ligand in metastatic triple-negative breast cancer

Abstract Background: Only a subset of patients with metastatic triple-negative breast cancers (TNBC) demonstrate response to FDA approved PD-1 immune checkpoint blockade (ICB), and few have durable responses. Data suggests that breast cancers have defects in antigen presentation and that antigen presenting cells especially the cDC1 subtype of dendritic cells (DCs) are required for response to ICB. CD40 agonists activate antigen presenting cells including DCs and B cells and repolarize macrophages to an anti-tumor phenotype. Flt3 ligand is a growth factor that increases differentiation and expansion of DCs. We recently demonstrated in pre-clinical TNBC models that the combination of liposomal doxorubicin chemotherapy, a CD40 agonist, and a Flt3 ligand improves outcomes compared to alternate combinations. Methods: This is a single arm phase I pilot study of liposomal doxorubicin, CDX-1140 (CD40 agonist monoclonal antibody), and CDX-301 (recombinant Flt3 ligand) combination therapy in patients with metastatic or unresectable locally advanced metastatic TNBC. Patients will be randomized to 3 lead-in arms (triplet therapy, doublet immunotherapy only, or liposomal doxorubicin only) for one cycle prior to receiving triplet therapy with tissue biopsies done before and after the lead-in treatment. CDX-301 will be given for only two cycles; liposomal-doxorubicin and CDX-1140 will be continued until disease progression or clinically limiting toxicities. Primary endpoint is determination of a recommended phase II dose based on treatment-related adverse events and dose-limiting toxicities. Secondary endpoints include anti-tumor immune response after triplet therapy, after immunotherapy alone, and after liposomal doxorubicin alone; median progression-free survival, overall response rate, duration of response, and clinical benefit rate. Key eligibility criteria are unresectable stage III or stage IV TNBC (ER ≤10%, PR ≤10%, HER2/neu negative), 1st to 3rd line treatment for metastatic disease (1st line patients need to be PD-L1 negative by 22C3 assay), measurable disease by RECIST 1.1 criteria, consent for pre-treatment and on-treatment biopsies of amenable soft tissue tumor lesions, no prior treatment with an anti-CD40 antibody or a Flt3 ligand, no anthracycline treatment in the metastatic setting, no prior progression while on anthracycline-based therapy or within 6 months of completing neoadjuvant chemotherapy, and no history of non-infectious pneumonitis or current pneumonitis. This trial will enroll up to 45 patients across multiple sites (NCT05029999) and is currently open at University of Texas Southwestern Medical Center, Texas Oncology, University of Chicago, University of Texas San Antonio, Sarah Cannon Research Institute, and Johns Hopkins. Citation Format: Sangeetha Reddy, Joyce O'Shaughnessy, Navid Sadeghi, Samira Syed, Cesar Santa-Maria, Virginia Kaklamani, Nan Chen, Denise Yardley, Yisheng Fang, Isaac Chan, Nisha Unni, Sarah Kashanian, Namrata Peswani, Shahbano Shakeel, Meredith Carter, Kelly Kyle, Farjana Fattah, Chul Ahn, Ina Patel, Joshua Gruber, Dawn Klemow, Glenda Delgado, Nicole Sinclair, Michael Yellin, Heather McArthur, Rita Nanda, Suzanne Conzen, Carlos Arteaga. Phase I trial of pegylated liposomal doxorubicin chemotherapy in combination with CD40 agonist and Flt3 ligand in metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-08.

Abstract CT277: BGB-LC-201 (NCT05635708): A phase 2, open-label, multi-arm study of tislelizumab (TIS; anti-PD-1) in combination with investigational agents +/- chemotherapy as first-line treatment for patients with locally advanced, unresectable, or metastatic non-small cell lung cancer (NSCLC)

Abstract Background: Prognosis for locally advanced, unresectable, or metastatic NSCLC remains poor despite advances in the use of immune checkpoint inhibitors (ICI) with or without histology-appropriate chemotherapy (chemo), partly due to innate or adaptive resistance to ICI. Combination therapies aim to overcome resistance to anti-programmed cell death protein-1 or programmed death-ligand-1 (PD-1/PD-L1) therapy and thus improve anticancer activity. This phase 2 study will determine whether adding investigational agents BGB-A445 (OX40 agonistic monoclonal antibody [mAb]), LBL-007 (anti-lymphocyte activation gene-3 mAb), or BGB-15025 (hematopoietic progenitor kinase 1 [HPK1] inhibitor) improves the therapeutic benefit of TIS (anti-PD-1 mAb) +/- chemo in patients with locally advanced, unresectable, or metastatic NSCLC. Methods: The umbrella design allows for the use of multiple investigational drugs, administered alone or in combination, in patients with untreated locally advanced, unresectable, or metastatic NSCLC without actionable driver mutations. Approximately 400 patients aged ≥18 years will be enrolled in 1 of 2 Substudies based on PD-L1 expression and randomized 2:1 to either the experimental or reference arm within each Substudy. Patients in Substudy 1 (PD-L1 ≥50%) will be randomized to receive either TIS (200 mg intravenously [IV] every 3 weeks [Q3W]) in combination with BGB-A445 (2400 mg IV Q3W), LBL-007 (600 mg IV Q3W), or BGB-15025 (experimental arms) or TIS monotherapy (reference arm). Those in Substudy 2 (PD-L1 <50%) will receive TIS + chemo in combination with BGB-A445 (2400 mg IV Q3W), LBL-007 (300 mg, 600 mg, or 1200 mg IV Q3W), or BGB-15025 (experimental arms) or TIS + chemo (reference arm). Patients will receive up to 36 cycles (each cycle lasting 3 weeks) or until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint is investigator-assessed confirmed overall response rate per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; secondary endpoints include investigator-assessed progression-free survival, duration of response, clinical benefit rate, disease control rate (per RECIST v1.1), pharmacokinetics, immunogenicity, and safety. Exploratory endpoints include overall survival, time to response, and relevant biomarker associations with response or resistance to study treatments. Enrollment is ongoing at 66 sites in China, Asia-Pacific, the United States, and the European Union. Citation Format: George Blumenschein, Benjamin Besse, Justin F. Gainor, DingZhi Huang, Steven Kao, Se-Hoon Lee, Luis Paz-Ares, Xin Chen, Wanyu He, Sridharan Gururangan, Kathy Zhang, Caicun Zhou. BGB-LC-201 (NCT05635708): A phase 2, open-label, multi-arm study of tislelizumab (TIS; anti-PD-1) in combination with investigational agents +/- chemotherapy as first-line treatment for patients with locally advanced, unresectable, or metastatic non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT277.

Abstract 6594: 4-1BB: A double-edged sword for T cells

Abstract Background: The costimulatory receptor 4-1BB (CD137) is expressed on the surface of activated T cells, playing a pivotal role in enhancing T cell responses and emerging as a promising target for cancer immunotherapy. Its primary ligand, 4-1BBL (CD137L), is found on antigen-presenting cells and various immune cells. The interaction between 4-1BBL and 4-1BB provides crucial costimulatory signals to both CD4+ and CD8+ T cells, amplifying their activation and effector functions. However, recent studies have shed light on a distinct role of 4-1BB in T cells. Prior work has revealed that 4-1BB can distinguish intratumoral regulatory T cells (Tregs) from peripheral Tregs and other CD4 lineage T cells in cancer patients, and the overexpression of 4-1BB on Tregs has been associated with unfavorable survival outcomes. Additionally, targeting 4-1BB with IgG2a isotype antibodies has shown significant anti-tumor efficacy in preclinical models by depleting Tregs. Furthermore, agonist monoclonal antibodies targeting 4-1BB have not only shown promise in inducing tumor regressions but also demonstrated improved outcomes in mouse models of autoimmune diseases induced by autoreactive CD4+ T cells. These findings indicate the existence of specific ligands or factors that modulate 4-1BB function on T cells that can vary depending on the disease state. Methods: To identify potential ligand(s) involved in the modulation of 4-1BB function, we developed an innovative CRISPR/Cas9-based transcriptional activation (CRISPRa) screening system that integrates CRISPR/Cas9-guide mediated gene activation, high avidity bead-based selection, serial enrichment, and flow cytometry-based monitoring. This screening platform provides enhanced sensitivity for identifying extracellular interactions between receptor-ligand partners that have not been fully characterized before, even with low-affinity. Results: Through our unbiased CRISPRa screen, we discovered that Myelin-Associated Glycoprotein (MAG), also known as siglec-4, a member of the siglec (sialic acid-binding immunoglobulin-like lectins) family, interacts with 4-1BB in trans. Our study demonstrated that MAG binds to activated T cells via 4-1BB and inhibits their activation and proliferation, suggesting a potential role of the MAG-4-1BB interaction in modulating T cell function. Notably, our data revealed that trans-binding to MAG-positive cells inhibits c-Jun signaling in activated T cells. Furthermore, the presence of MAG on target cells can hinder Chimeric Antigen Receptor (CAR) T-cell activity. Conclusion: Utilizing a highly efficient cell-based CRISPRa system, we discovered a novel interactor of 4-1BB capable of modulating T cell activation through its interaction with 4-1BB. This interaction suggests an immunosuppressive role of 4-1BB, explaining the paradoxical roles of 4-1BB in T cells. These findings provide crucial insights for the development of precise therapeutics targeting 4-1BB. Citation Format: Liping Yang, Timothy P. Sheets, Yang Feng, Kuo-Sheng Hsu, Guojun Yu, Steven Seaman, Pradip Bajgain, Daeho So, Jaewon Lee, Raj Chari, Brad St. Croix. 4-1BB: A double-edged sword for T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6594.

Abstract 5301: Tumor-targeted activation of CD137 using Bicycles: New insights into mechanism of action and discovery of BT7455, a clinical candidate for the treatment of EphA2-expressing cancers

Abstract Introduction: Clinical studies in cancer patients have validated CD137 agonism as an activator of the immune system to enable tumor rejection. We have demonstrated that small, chemically synthetic bicyclic peptides can drive tumor-localized agonism of CD137 and anti-tumor immunity in mouse models. Here, we report the next stage of our work - delving into the mechanism of action of these novel agents and extending our program to serve patients whose tumors express EphA2. Experimental Procedures: MultiOmyx™ hyperplexed immunofluorescence assay was used to evaluate the expression of CD137 and EphA2 in head and neck squamous cell carcinoma samples. Human PBMC/tumor cell co-culture assays were used to assess CD137 Bicycle TICA™ in vitro bioactivity and syngeneic mouse tumor models were used to evaluate CD137 Bicycle TICA anti-tumor activity as mono- or combination therapies. Pharmacodynamic activity was evaluated by transcriptional profiling using NanoString assays or single cell RNA sequencing. Summary of the Data: Studies utilizing a syngeneic mouse model and deep RNA sequencing of tumors from CD137 Bicycle TICA-treated mice implicated intratumoral dendritic cells in addition to T cells as early responders to localized CD137 agonism and potential contributors to the anti-tumor response. Furthermore, a mouse efficacy model demonstrated synergy with checkpoint inhibitor therapy. Multiplex imaging revealed that EphA2 and CD137 are co-expressed in human tumors of high unmet medical need and therefore, using our highly modular Bicycle platform, we discovered BT7455, a Bicycle TICA that engages EphA2 and CD137 with high affinity, resulting in potent EphA2-dependent activity in vitro and robust anti-tumor activity in vivo with intermittent dosing in mouse models. Gene expression profiling of tumors revealed that BT7455 led to increased production of cytokines and chemokines known to drive T cell infiltration, the extent of which differentiated it from both a checkpoint inhibitor and an anti-CD137 monoclonal antibody agonist. BT7455 was well tolerated in preclinical species and liver function tests indicated no evidence of hepatic toxicity. Statement of Conclusions: In summary, we have identified EphA2 as a promising target to pair with a CD137 agonist. In addition to CD8+ T cells, tumor-resident dendritic cells are a likely contributor to anti-tumor immunity following treatment with Bicycle® TICAs, supporting utility for Bicycle® tumor-targeted CD137 agonists in solid tumors beyond those that are highly T cell-infiltrated. We have advanced a clinical development candidate, BT7455, to realize this potential for patients with EphA2-expressing cancers. Citation Format: Johanna Lahdenranta, Kristen Hurov, Heather Cohen, Lia Luus, Cara Bray, Peter Brown, Anna Devlen, Carly Campbell, Matthew Gray, Mike Kelly, Gemma Mudd, Punit Upadhyaya, Sailaja Battula, Kelvin Zhang, Anne-Sophie Dugast, Kevin McDonnell, Phil Brandish, Nicholas Keen. Tumor-targeted activation of CD137 using Bicycles: New insights into mechanism of action and discovery of BT7455, a clinical candidate for the treatment of EphA2-expressing cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5301.

Final results of urelumab, an anti-CD137 agonist monoclonal antibody, in combination with cetuximab or nivolumab in patients with advanced solid tumors

BackgroundResistance to immune checkpoint inhibitors and targeted treatments for cancer is common; thus, novel immunotherapy agents are needed. Urelumab is a monoclonal antibody agonist that binds to CD137 receptors expressed...

Neoadjuvant CD40 Agonism Remodels the Tumor Immune Microenvironment in Locally Advanced Esophageal/Gastroesophageal Junction Cancer.

Sotigalimab is an agonistic anti-CD40 mAb that can modulate antitumor immune responses. In a phase II clinical trial of sotigalimab combined with neoadjuvant chemoradiation (CRT) in locally advanced esophageal/gastroesophageal junction (E/GEJ) cancer with the primary outcome of efficacy as measured by pathologic complete response (pCR) rate, the combination induced pCR in 38% of treated patients. We investigated the mechanism of action of sotigalimab in samples obtained from this clinical trial. Tumor biopsies and peripheral blood samples were collected at baseline, following an initial dose of sotigalimab, and at the time of surgery after CRT completion from six patients. High dimensional single-cell techniques were used, including combined single-cell RNA-sequencing and proteomics (CITEseq) and multiplexed ion beam imaging, to analyze immune responses. Sotigalimab dramatically remodeled the immune compartment in the periphery and within the tumor microenvironment (TME), increasing expression of molecules related to antigen processing and presentation and altering metabolic pathways in myeloid cells. Concomitant with these changes in myeloid cells, sotigalimab treatment primed new T cell clonotypes and increased the density and activation of T cells with enhanced cytotoxic function. Sotigalimab treatment also induced a decrease in the frequency of Tregs in the TME. These findings indicate that a single dose of sotigalimab leads to enhanced antigen presentation that can activate T cells and induce new T cell clones. This restructuring of the TME provides elements which are critical to the development of effective antitumor immune responses and improved clinical outcomes.

DOP81 Rosnilimab, a novel PD-1 agonist monoclonal antibody, reduces T cell proliferation, inflammatory cytokine secretion, and PD-1high expressing CD4 and CD8 T cells: Results from a Phase 1 healthy volunteer clinical trial

Abstract Background Programmed cell death protein 1 (PD-1) is expressed on activated T cells and is a key co-inhibitory node in immune regulation. By targeting regulatory mechanisms to modulate immune cells driving disease, there is an opportunity to restore immune balance. Rosnilimab is a PD-1 agonist antibody designed to reduce T cell proliferation and inflammatory cytokine secretion and deplete PD-1high T follicular helper, T peripheral helper, and T effector cells. It is being studied for ulcerative colitis (UC), where PD-1+ T cells are prevalent in inflamed lamina propria (>40%) and the periphery. The primary objective of this healthy volunteer Phase 1 study was to assess the safety and tolerability of single ascending doses (SAD) and multiple ascending doses (MAD) of rosnilimab. Findings from pharmacokinetic (PK) and pharmacodynamic (PD) assessments are summarized. Methods This single-centre study included 14 cohorts in SAD and 3 cohorts in MAD. Each cohort had 8 participants (6 active, 2 placebo [PBO]). Cohorts were enrolled sequentially in each phase. Intravenous (IV) and subcutaneous (SC) administration were assessed in SAD; SC route was assessed in MAD. Results A total of 144 participants were enrolled; 90 to active SAD cohorts, 18 to active MAD cohorts, and 30 and 6 to SAD and MAD PBO cohorts, respectively. Rosnilimab was well tolerated with no dose-limiting toxicities or deaths. Two serious adverse events were reported in SAD (deemed unrelated to treatment) and 0 in MAD. PD-1 expressing cells were reduced by ~50% in both CD4+ and CD8+ subsets, in a dose-dependent manner and in correlation with full receptor occupancy (RO) through Day 30 in SAD. PD activity was rapid with sustained reduction in PD-1+ T cells, and ex-vivo stimulation resulted in reduced T cell functional activity. This reduction was maximized on PD-1high expressing T cells: ~90% reduction vs baseline. There was no significant impact on the overall total T cell or regulatory T (Treg) cell numbers, resulting in restoration of T cell composition to a less activated state and a positive shift in the Treg:Teff ratio. An antigen-specific functional T cell assay measuring ex vivo interferon-gamma release in response to antigen challenge was inhibited up to ~90% vs baseline and the response lasted for more than 30 days following a single dose. Rosnilimab had a favourable PK profile consistent with full RO, a 2-week half-life, and dose-proportional exposure in IV and SC dosing. Conclusion Rosnilimab demonstrated favourable safety, PK, and PD activity. The role of PD-1 in UC pathophysiology coupled with these results and translational data, demonstrate proof of mechanism and support progression into a Phase 2 study of rosnilimab in UC. (NCT06127043)

Programmed death receptor 1 (PD-1) ligand Fc fusion proteins reduce T-cell proliferation in vitro independently of PD-1.

Programmed death receptor 1 (PD-1) is an inhibitory receptor on T cells shown to restrain T-cell proliferation. PD-1 immune checkpoint blockade has emerged as a highly promising approach in cancer treatment. Much of our understanding of the function of PD-1 is derived from in vitro T-cell activation assays. Here we set out to further investigate how T cells integrate inhibitory signals such as PD-1 in vitro using the PD-1 agonist, PD-1 ligand 1 (PD-L1) fusion protein (PD-L1.Fc), coimmobilized alongside anti-CD3 agonist monoclonal antibody (mAb) on plates to deliver PD-1 signals to wild-type and PD-1-/- CD8+ T cells. Surprisingly, we found that the PD-L1.Fc fusion protein inhibited T-cell proliferation independently of PD-1. This PD-L1.Fc inhibition was observed in the presence and absence of CD28 and interleukin-2 signaling. Binding of PD-L1.Fc was restricted to PD-1-expressing T cells and thus inhibition was not mediated by the interaction of PD-L1.Fc with CD80 or other yet unknown binding partners. Furthermore, a similar PD-1-independent reduction of T-cell proliferation was observed with plate-bound PD-L2.Fc. Hence, our results suggest that the coimmobilization of PD-1 ligand fusion proteins with anti-CD3 mAb leads to a reduction of T-cell engagement with plate-bound anti-CD3 mAb. This study demonstrates a nonspecific mechanism of T-cell inhibition when PD-L1.Fc or PD-L2.Fc fusion proteins are delivered in a plate-bound coimmobilization assay and highlights the importance of careful optimization of assay systems and reagents when interpreting their influence on T-cell proliferation.

Abstract A032: Antitumor activities of different RIG-I agonists in a murine model of kidney adenocarcinoma

Abstract Purpose: Activation of retinoic acid-inducible gene I (RIG-I) signaling induces tumor cell apoptosis and enhances NK, dendritic, and effector T cell activity. We applied two distinct RIG-I agonists: purified influenza virus RNA (IV RNA) in combination with an agonistic OX40 receptor-specific monoclonal antibody (anti-OX40) and a 3p-hpRNA (5' triphosphate hairpin RNA) combined with unmethylated CpG oligonucleotide (CpG). We also investigated the CpG and anti-OX40 combination. The study aimed to establish the efficacy of these compounds in a murine model of kidney adenocarcinoma (Renca). Methods: Renca cells were subcutaneously engrafted in 40 BALB/c mice. The animals were allocated into three treatment groups and a control group. Intratumoral administration of specific adjuvant combinations was carried out thrice as follows: Group 1: CpG+anti-OX40, Group 2: CpG+3p-hpRNA, Group 3: IV RNA+anti-OX40, and Group 4: PBS. Daily monitoring encompassed assessment of primary tumor sizes and physiological parameters. Deceased mice underwent dissection, and histological evaluations were performed. Treatment efficacy was ascertained based on tumor growth, distant metastases' occurrence, and cytokine levels' alterations. Statistical analysis was conducted, with p-values<0.05 considered statistically significant. Results: On day 38 post-implantation, the survival rates for the various groups were as follows: Group 4: 20%, Group 1: 70% (sig), Group 2: 50% (ns), and Group 3: 60% (sig). Measurements of primary tumor sizes were conducted following the final treatment on day 17 and subsequently every seven days until day 38. On day 17, no significant disparities in primary tumor sizes were observed between Groups 1, 2, 3, and 4. However, on day 24, Groups 1, 2, and 3; on day 31, Groups 1 and 2 exhibited significantly smaller primary tumors than Group 4. By day 38, no significant differences in tumor sizes were evident among the groups. Notably, discernible variations in primary tumor characteristics were observed: Groups 1, 2, and 3 demonstrated incipient demarcation, whereas Group 4 exhibited diffuse primary tumors accompanied by necrosis. Concerning metastatic development, the results are currently under evaluation and will be available for presentation at the conference, alongside the outcomes of cytokine ELISA tests. Discussion: After concluding the experiment, we deem the treatments to hold considerable promise. Notably, while the treatment effects were sustained, tangible outcomes were achieved: prolonged survival of the mice, reduction in primary tumor sizes, and mitigated metastatic formation. However, following the final treatment, there was a notable decline in the animals' overall quality of life. Consequently, we decided to terminate the experiment. In light of our findings, we ascertain that the treatments serve as a solid foundation for further exploration. By modifying the composition of the treatment cocktails and adjusting the treatment frequency, there exists the potential for further enhancement of the achieved results. Citation Format: Dominik Gulyás, Márta Lőrincz, István Jankovics, Béla Dénes, Dóra Földi, Rhiannon Rodgers, Katie Commins, Gábor Andócs, Gábor Kovács. Antitumor activities of different RIG-I agonists in a murine model of kidney adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A032.

Abstract B034: CD27 is a new promising T cell co-stimulatory target for cancer immunotherapy

Abstract Members of the tumor necrosis factor receptor superfamily (TNFRSF) are key co-stimulators of T cells. CD27, a member of the TNFRSF, is expressed only on the surface of lymphocytes, including naive and activated CD4+ and CD8+ T cells as well as NK cells. It enhances T cell activation, proliferation, and differentiation of effector and memory T cells after stimulation with its ligand, CD70. The costimulatory signal of CD27 is mediated via the NFkB pathway but also via the phosphatidylinositol 3 kinase and the protein kinase B pathways. CD27 signaling also influences the innate immune response via direct activation of NK cells and subsequent secretion of interferon-gamma (IFNg). Several published preclinical studies demonstrated that anti-CD27 agonistic monoclonal antibodies can promote T-cell activation and antitumor immunity making CD27 an attractive cancer immunotherapy target. Here we describe the characterization, preclinical development, and selection of our anti-CD27 fully human monoclonal antibody (mAb) lead candidate. We selected this candidate from a library of 147 anti-CD27 mAbs generated after immunization of humanized Trianni® mice with soluble human CD27 extracellular domain (hCD27-ECD). Anti-CD27 mAbs were tested in an accelerated stability study and showed excellent stability parameters for up to 7 days at 4 and 37°C in commonly used formulation buffers. The selected agonist anti-CD27 mAb demonstrated high affinity binding to both human and cynomolgus monkey CD27 and not to mouse CD27. It also demonstrated high specificity against CD27 with no cross-reactivity detected against other members of the TNFRSF. This lead candidate did not block the binding of CD27 natural ligand, CD70 and induced strong NFkB-mediated CD27 signaling in the absence or presence of cross-linking by Fc gamma receptors or secondary cross-linking antibodies. Moreover, this anti-CD27 mAb mediated NFkB activation is significantly potentiated by the addition of a sub-optimal amount of soluble CD70. The anti-CD27 lead mAb induced T cell proliferation and secretion of pro-inflammatory cytokines only in the presence of sub-optimal TCR stimulation in vitro using primary human T cells. It also activated NK cells demonstrated by CD69 expression induction. The anti-CD27 mAb lead candidate showed extended serum half-life in hCD27-KI mice. It also demonstrated a significant antitumor effect as a single agent in human CD27-Knockin mice (hCD27-KI) subcutaneously implanted with MC38 or in NOD-SCID mice subcutaneously implanted with Raji. These preclinical results establish that the selected anti-CD27 mAb is a promising drug candidate and we are actively pursuing its development. Citation Format: Thierry Guillaudeux, Yulia Ovechkina, Kurt Lustig, Shawn Iadonato. CD27 is a new promising T cell co-stimulatory target for cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B034.

Reduction of renal interstitial fibrosis by targeting Tie2 in vascular endothelial cells

BackgroundTie2, a functional angiopoietin receptor, is expressed in vascular endothelial cells and plays an important role in angiogenesis and vascular stability. This study aimed to evaluate the effects of an agonistic Tie2 signal on renal interstitial fibrosis (RIF) and elucidate the underlying mechanisms.MethodsWe established an in vivo mouse model of folic acid-induced nephropathy (FAN) and an in vitro model of lipopolysaccharide-stimulated endothelial cell injury, then an agonistic Tie2 monoclonal antibody (Tie2 mAb) was used to intervent these processes. The degree of tubulointerstitial lesions and related molecular mechanisms were determined by histological assessment, immunohistochemistry, western blotting, and qPCR.ResultsTie2 mAb attenuated RIF and reduced the level of fibroblast-specific protein 1 (FSP1). Further, it suppressed vascular cell adhesion molecule-1 (VCAM-1) and increased CD31 density in FAN. In the in vitro model, Tie2 mAb was found to decrease the expression of VCAM-1, Bax, and α-smooth muscle actin (α-SMA).ConclusionsThe present findings indicate that the agonistic Tie2 mAb exerted vascular protective effects and ameliorated RIF via inhibition of vascular inflammation, apoptosis, and fibrosis. Therefore, Tie2 may be a potential target for the treatment of this disease.ImpactThis is the first report to confirm that an agonistic Tie2 monoclonal antibody can reduce renal interstitial fibrosis in folic acid-induced nephropathy in mice.This mechanism possibly involves vascular protective effects brought about by inhibition of vascular inflammation, apoptosis and fibrosis.Our data show that Tie2 signal may be a novel, endothelium-specific target for the treatment of tubulointerstitial fibrosis.

Abstract 13840: Safety Outcomes From a First-in-Human Study of a Novel Investigational Monoclonal Antibody, REGN5381, an Agonist to the Natriuretic Peptide Receptor 1

Introduction: Natriuretic peptides (NPs) regulate vascular volume and tone via the membrane-bound guanylate cyclase, natriuretic peptide receptor 1 (NPR1). Activation of this pathway is known to lower systemic and venous blood pressure (BP) and effect natriuresis and diuresis. Previous recombinant NP infusions for heart failure were limited by their duration of effects. REGN5381, a novel investigational NPR1 agonist monoclonal antibody, showed sustained hemodynamic effects in animal models. Here, we report safety and pharmacodynamic (PD) outcomes from a phase 1, first-in-human study of REGN5381. Hypothesis: REGN5381 is sufficienty well tolerated in healthy humans to warrant continued clinical investigation. Aim: To assess the safety, tolerability, and REGN5381 PD in normotensive humans. Methods: This double-blind, single-ascending dose study (NCT04506645), randomized healthy adults aged 18-55 years (6:2) to receive a single intravenous dose of REGN5381 or placebo. Participants received a fixed-sodium and fluid diet and remained 4 days in the clinic for non-invasive hemodynamics monitoring and safety assessment. Results: A total of 48 participants were enrolled; 12 were randomized to placebo and 6 to each of 6 REGN5381 dose levels (total n=36). Eight (66.7%) participants in the placebo and 24 (66.7%) in the total REGN5381 group reported ≥1 treatment-emergent adverse event (TEAE), with no obvious relationship to dose level. Four (33.3%) participants in the placebo and 15 (41.7%) in the total REGN5381 group reported ≥1 study drug related TEAE, with no obvious relationship to dose level. Common TEAEs (experienced by >10% of participants in the total group) were postural dizziness (placebo: 2 [16.7]%; total REGN5381: 6 [16.7]%) and headache (placebo: 5 [41.7%]; total REGN5381: 4 [11.1%]). Pyuria and orthostatic hypotension were reported in 4 (11.1%) participants in the total group, but none in the placebo group. No serious or severe TEAEs or deaths were reported in any dose groups. Participants treated with the highest dose saw a 7-11 mmHg reduction of systolic BP that was sustained over 72 hours (the full duration of inpatient monitoring). Conclusion: A single dose of REGN5381 is generally well-tolerated and provides sustained hemodynamic effects.

88 ANB032, a novel BTLA agonist monoclonal antibody, inhibits T cell proliferation, reduces inflammatory cytokines, and down modulates BTLA expression on circulating T and B cells

88 ANB032, a novel BTLA agonist monoclonal antibody, inhibits T cell proliferation, reduces inflammatory cytokines, and down modulates BTLA expression on circulating T and B cells

FRI057 Drug Concentrations And Dosing Considerations For Mibavademab, A Novel Leptin Receptor Agonist, In Individuals With Generalized Lipodystrophy

Abstract Disclosure: J. Mendell: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. Y. Wang: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. B.A. Olenchock: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Podgrabinska: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. O.E. Pagovich: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. E.A. Oral: Advisory Board Member; Self; Regeneron Pharmaceuticals. Consulting Fee; Self; Third Rock Ventures, Rejuvenate Inc. Grant Recipient; Self; Amryt Pharamceuticals, Ionis Pharmaceuticals Inc., Gemphire Theraputics. Research Investigator; Self; Regeneron Pharmaceuticals, Novo Nordisk, Rhythm pharmaceuticals, Fractyl Laboratories, GI Dynamics. Other; Self; Has IP rights to Metreleptin manufactured by Amryt Pharmaceuticals and receives royalty payments. R.J. Brown: Research Investigator; Self; Regeneron Pharmaceuticals. J. Davis: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. Background: Generalized lipodystrophy (GLD) is characterized by deficiency of adipose tissue and, consequently, low levels of the adipose-derived hormone leptin. Leptin deficiency in GLD causes metabolic abnormalities and complications that are often refractory to treatment with usual glucose/lipid-lowering agents. Mibavademab is a first-in-class human leptin receptor (LEPR) agonist monoclonal antibody that activates LEPR. We investigated baseline serum leptin in patients with GLD, pharmacokinetics (PK) of mibavademab, and soluble LEPR (sLEPR) levels from a phase 2 study. Methods: In this phase 2 trial (NCT04159415), patients with GLD (≥12 yrs old) underwent a single-blind placebo run-in, followed by 1:1 randomization to one of two fixed sequence arms: Treatment A (placebo for 8 weeks, then mibavademab low dose for 8 weeks, then mibavademab high dose for 20 weeks) or Treatment B (mibavademab low dose for 8 weeks, then mibavademab high dose for 28 weeks). A loading dose of intravenous mibavademab was administered before low-dose treatment. Mibavademab and sLEPR concentrations in serum were serially measured during mibavademab treatment using validated bioanalytical methods. Results: Sixteen patients were enrolled with median body weight (BW) of 51 kg, corresponding to the approximate BW cut point for mibavademab. Baseline serum leptin was below the lower limit of quantitation (0.078 mg/L) in 5 patients with a median concentration of 0.345 mg/L (n=15). Baseline sLEPR concentrations with Treatments A and B were 30.6 and 33.9 μg/L, respectively. At Week 8, mean (SD) mibavademab trough concentrations (Ctrough) with Treatments A and B were 0 (0) and 1.61 (1.71) mg/L, respectively. Low-dose PK were less than predicted from a first in human study in healthy volunteers with higher leptin levels, reflecting higher target mediated clearance in patients with GLD. At Week 16, Ctrough for Treatments A and B increased to 2.31 and 43.0 mg/L, respectively, but were still below predicted. At Week 36, Ctrough for Treatments A and B were 60 (35.3) and 67.7 (44.2) mg/L, respectively. Clinically meaningful metabolic benefit (i.e reflected by reductions in fasting triglycerides and glycated hemoglobin) was observed at Week 36 with both Treatments A and B. Conclusions: Mibavademab concentrations by Week 36 were associated with clinically meaningful improvement in metabolic parameters. Presentation: Friday, June 16, 2023

FRI069 Treatment With Mibavademab, A Novel Leptin Receptor Agonist, Is Associated With Improvement In Weight And Associated Comorbidities In Congenital Leptin Deficiency

Abstract Disclosure: E. Ozsu: None. L. Akin: None. M. Aydin: None. M. Berberoglu: None. D. Stein: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. O. Pagovich: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. B. Olenchock: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Podgrabinska: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. C.A. Harris: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. J. Mendell: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. R. SinhaRoy: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. J. Altarejos: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. B. Akinci: Advisory Board Member; Self; Amryt Pharmaceuticals, Regeneron, Third Rock Ventures. Consulting Fee; Self; Third Rock ventures, Regeneron, Amryt Pharmaceuticals. Speaker; Self; Astra Zeneca, Lilly, MSD, Novartis, Novo Nordisk, Sanofi Aventis. E.A. Oral: Advisory Board Member; Self; Third Rock Ventures, Regeneron, Rejuveneate Bio. Consulting Fee; Self; Amryt Pharmaceuticals, Regeneron. Grant Recipient; Self; Regeneron, Novo Nordisk, GI Dynamics, Ionis Pharmaceuticals, Fractyl, Rhythm Pharmaceuticals. Other; Self; Amryt Pharmaceuticals. Background: Congenital leptin deficiency (CLD) is a form of extreme obesity caused by biallelic pathogenic variants in the leptin gene. Recombinant human leptin normalizes weight and neuroendocrine/metabolic abnormalities in CLD, however, daily dosing is required with a risk of immunogenicity. Mibavademab is an investigational human leptin receptor agonist monoclonal antibody. Case report: A Turkish male infant came to medical attention due to rapid weight gain at 2 months of age and work-up led to identification of homozygous variant in the leptin gene causing CLD. He was treated with Metreleptin for 11 months starting at age 2. When weight regain despite Metreleptin therapy was noted, neutralizing antibody (Nab) was found to be strongly positive. He continued to gain weight rapidly causing impaired mobility, and required nightly oxygen with BIPAP. He was hospitalized frequently with upper respiratory tract infections and needed ICU care four times during the 5th year of his life. At age 5 years and 9 months and body weight of 89.9 kg (BMI SD:5.7), the compassionate use application to use Mibavademab was approved by the local ethics board and the Ministry of Health. The patient received an intravenous loading dose of Mibavademab followed by weekly subcutaneous (SC) administration of Mibavademab. SC dose and diet intake were carefully adjusted based on drug levels, and intended vs. observed weight loss. Results: Weight reduction was first observed in the first week of treatment, which was rapid with an average velocity of 7.1 kg/month until month 7. Upon dose adjustment, velocity decreased to 3.1 kg/month. Weight stabilization was achieved at month 11 at a weight of 28.9 kg (BMI SD:1.0) while using Mibavademab every two weeks. Overall, drug levels were significantly higher than projected in the first 28 weeks and then brought to predicted stable levels upon dose adjustments. Despite the rapid weight loss, improved mobility and age-appropriate growth were observed. There were no signs of precocious puberty. Glucose tolerance, insulinemia, and liver parameters all improved favorably over treatment period and there were no safety signals. The patient discontinued BIPAP treatment and sleep assumed a normal pattern without hypoxia. Conclusions: Compassionate treatment with Mibavademab for up to 60 weeks was associated with improvements in body weight and metabolic parameters, and was well-tolerated in a young child with CLD and Nab against metreleptin. Substantial benefits in mobility, social engagement, and respiratory status were also noted without adverse events. Mibavademab represents a potential new therapeutic option for patients with CLD and this first experience will provide guidance for treatment of similar patients. Presentation: Friday, June 16, 2023

FRI058 Treatment With Mibavademab, A Novel Leptin Receptor Agonist, Is Associated With Improvement In Metabolic Parameters In Individuals With Generalized Lipodystrophy

Abstract Disclosure: B. Olenchock: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Podgrabinska: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. C. Hou: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. B. Musser: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. J. Mendell: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. A. Harman: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. R.J. Sanchez: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. K. Miller: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. P. Parasoglou: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Hectors: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Karnik: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. O.E. Pagovich: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. R. SinhaRoy: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. C.A. Harris: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. B. Akinci: Advisory Board Member; Self; Regeneron Pharmaceuticals, Amryt Pharmaceuticals. Consulting Fee; Self; Amryt Pharmaceuticals, Regeneron Pharmaceuticals, Third Rock Ventures, AstraZeneca, Lilly USA, LLC, Novartis Pharmaceuticals, Novo Nordisk, Boehringer Ingelheim, Servier, Sanofi-Aventis, MSD. I. Yildirim simsir: None. S. Ozen: None. E. Sorkina: Advisory Board Member; Self; Amryt Pharmaceuticals, Regeneron Pharmaceuticals. A. Garg: Consulting Fee; Self; Aegerion Pharmaceuticals, Regeneron Pharmaceuticals. Grant Recipient; Self; Aegerion Pharmaceuticals, Pfizer, Inc., Regeneron Pharmaceuticals, Amryt Pharmaceuticals, Ionis Pharmaceuticals Inc. R.J. Vargas Gonzalez: None. D.M. Weinreich: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. G. Herman: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. E.A. Oral: Consulting Fee; Self; Regeneron Pharmaceuticals, Third Rock Ventures, Amryt Pharmaceuticals, Rejuvenate Inc, Ionis Pharmaceuticals. Grant Recipient; Self; Gemphire Theraputics, Amryt Pharmaceuticals, Ionis Pharmaceuticals. R.J. Brown: Grant Recipient; Self; Regeneron Pharmaceuticals. Background: Generalized lipodystrophy (GLD) is characterized by the deficiency of adipose tissue and consequently, low levels of the adipose-derived hormone leptin. Leptin deficiency in GLD leads to metabolic abnormalities which are often refractory to treatment with conventional agents. Recombinant human leptin, the only approved therapeutic, improves metabolic abnormalities of GLD, however, daily dosing is required and there is a risk of immunogenicity. There is an unmet need for effective therapies in GLD that are safe, administered less frequently, and can treat patients who have developed neutralizing antibodies to recombinant leptin. Mibavademab is an investigational human leptin receptor agonist monoclonal antibody. We report here the safety, tolerability and pharmacodynamic (PD) responses to mibavademab in a Phase 2 trial (NCT04159415) in patients with GLD. Methods: Patients ≥12 years with acquired or congenital GLD were randomized to mibavademab or placebo. After a single-blind placebo run-in, patients were randomized 1:1 to one of two fixed sequence arms comprising sequential 8-week treatment periods (Arm A: placebo, low-dose mibavademab, high-dose mibavademab; Arm B: low-dose mibavademab, high-dose mibavademab, high-dose mibavademab). Patients in each arm received an IV loading dose of placebo or mibavademab followed by weekly SC administration of study drug tiered by body weight (≥50 kg or <50 kg). Both arms were followed by an open-label high-dose mibavademab treatment period. Safety, pharmacokinetics, and PD of mibavademab were assessed. Primary efficacy endpoints, glycated hemoglobin (HbA1c) and fasting triglycerides (TGs) were measured at Week 8 and at predetermined time points thereafter until study completion. Results: Sixteen patients with GLD and baseline diabetes (mean HbA1c 9.6%, range 6.0%-12.2%) or hypertriglyceridemia (median TGs 669 mg/dL, range 107-2899 mg/dL) were randomized and completed ≥28 weeks of mibavademab treatment. After 8 weeks of low-dose mibavademab, drug levels were significantly lower than predicted in the active arm, and clinically meaningful differences were not observed for any of the primary efficacy endpoints as compared to placebo. In an exploratory pooled analyses after 28 weeks of mibavademab administration, serum drug concentrations were significantly higher than observed at Week 8, and clinically significant reductions from baseline in HbA1c (mean: -1.9%, SD: 2.0) and in TGs (median: -102.1 mg/dL, IQR: 1355.5 mg/dL, -49.3% [57.2%]). Mibavademab was generally well tolerated with no serious adverse events related to administration. Conclusions: Treatment with high-dose mibavademab for up to 28 weeks was associated with clinically meaningful improvements in metabolic parameters, and was generally well-tolerated. Mibavademab represents a potential new therapeutic option for patients with GLD. Presentation: Friday, June 16, 2023

The efficacy of a TrkB monoclonal antibody agonist in preserving the auditory nerve in deafened guinea pigs

The auditory nerve typically degenerates following loss of cochlear hair cells or synapses. In the case of hair cell loss neural degeneration hinders restoration of hearing through a cochlear implant, and in the case of synaptopathy suprathreshold hearing is affected, potentially degrading speech perception in noise. It has been established that neurotrophins such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) can mitigate auditory nerve degeneration. Several potential BDNF mimetics have also been investigated for neurotrophic effects in the cochlea. A recent in vitro study showed favorable effects of M3, a TrkB monoclonal antibody agonist, when compared with BDNF. In the present study we set out to examine the effect of M3 on auditory nerve preservation in vivo. Thirty-one guinea pigs were bilaterally deafened, and unilaterally treated with a single 3-µl dose of 7 mg/ml, 0.7 mg/ml M3 or vehicle-only by means of a small gelatin sponge two weeks later. During the experiment and analyses the experimenters were blinded to the three treatment groups. Four weeks after treatment, we assessed the treatment effect (1) histologically, by quantifying survival of SGCs and their peripheral processes (PPs); and (2) electrophysiologically, with two different paradigms of electrically evoked compound action potential (eCAP) recordings shown to be indicative of neural health: single-pulse stimulation with varying inter-phase gap (IPG), and pulse-train stimulation with varying inter-pulse interval. We observed a consistent and significant preservative effect of M3 on SGC survival in the lower basal turn (approximately 40% more survival than in the untreated contralateral cochlea), but also in the upper middle and lower apical turn of the cochlea. This effect was similar for the two treatment groups. Survival of PPs showed a trend similar to that of the SGCs, but was only significantly higher for the highest dose of M3. The protective effect of M3 on SGCs was not reflected in any of the eCAP measures: no statistically significant differences were observed between groups in IPG effect nor between the M3 treatment groups and the control group using the pulse-train stimulation paradigm. In short, while a clear effect of M3 was observed on SGC survival, this was not clearly translated into functional preservation.

1041P Phase I open-label, dose escalation and expansion study of YH003, an anti-CD40 agonist monoclonal antibody in combination with toripalimab in patients (pts) with advanced solid tumours

1041P Phase I open-label, dose escalation and expansion study of YH003, an anti-CD40 agonist monoclonal antibody in combination with toripalimab in patients (pts) with advanced solid tumours