{"doi":"10.3389/fimmu.2024.1362775","title":"A phase I trial of SON-1010, a tumor-targeted, interleukin-12-linked, albumin-binding cytokine, shows favorable pharmacokinetics, pharmacodynamics, and safety in healthy volunteers","abstract":"<jats:sec><jats:title>Background</jats:title><jats:p>The benefits of recombinant interleukin-12 (rIL-12) as a multifunctional cytokine and potential immunotherapy for cancer have been sought for decades based on its efficacy in multiple mouse models. Unexpected toxicity in the first phase 2 study required careful attention to revised dosing strategies. Despite some signs of efficacy since then, most rIL-12 clinical trials have encountered hurdles such as short terminal elimination half-life (T<jats:sub>½</jats:sub>), limited tumor microenvironment targeting, and substantial systemic toxicity. We developed a strategy to extend the rIL-12 T<jats:sub>½</jats:sub> that depends on binding albumin <jats:italic>in vivo</jats:italic> to target tumor tissue, using single-chain rIL-12 linked to a fully human albumin binding (F<jats:sub>H</jats:sub>AB) domain (SON-1010). After initiating a dose-escalation trial in patients with cancer (SB101), a randomized, double-blind, placebo-controlled, single-ascending dose (SAD) phase 1 trial in healthy volunteers (SB102) was conducted.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>SB102 (NCT05408572) focused on safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) endpoints. SON-1010 at 50-300 ng/kg or placebo administered subcutaneously on day 1 was studied at a ratio of 6:2, starting with two sentinels; participants were followed through day 29. Safety was reviewed after day 22, before enrolling the next cohort. A non-compartmental analysis of PK was performed and correlations with the PD results were explored, along with a comparison of the SON-1010 PK profile in SB101.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Participants receiving SON-1010 at 100 ng/kg or higher tolerated the injection but generally experienced more treatment-emergent adverse effects (TEAEs) than those receiving the lowest dose. All TEAEs were transient and no other dose relationship was noted. As expected with rIL-12, initial decreases in neutrophils and lymphocytes returned to baseline by days 9-11. PK analysis showed two-compartment elimination in SB102 with mean T<jats:sub>½</jats:sub> of 104 h, compared with one-compartment elimination in SB101, which correlated with prolonged but controlled and dose-related increases in interferon-gamma (IFNγ). There was no evidence of cytokine release syndrome based on minimal participant symptoms and responses observed with other cytokines.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>SON-1010, a novel presentation for rIL-12, was safe and well-tolerated in healthy volunteers up to 300 ng/kg. Its extended half-life leads to a prolonged but controlled IFNγ response, which may be important for tumor control in patients.</jats:p></jats:sec><jats:sec><jats:title>Clinical trial registration</jats:title><jats:p><jats:uri>https://clinicaltrials.gov/study/NCT05408572</jats:uri>, identifier NCT05408572.</jats:p></jats:sec>","journal":"Frontiers in Immunology","year":2024,"id":617680,"datarank":0.32577366185147877,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.033887139493181714,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.033887139493181714,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":5,"citers_with_citation_signal":3,"citers_with_endowment":3,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1593060,"name":"John K. Cini","orcid":null,"position":1,"is_corresponding":false},{"id":1593062,"name":"Susan Dexter","orcid":null,"position":2,"is_corresponding":false},{"id":1593063,"name":"Manuel DaFonseca","orcid":null,"position":3,"is_corresponding":false},{"id":1593064,"name":"Justus Bingham","orcid":null,"position":4,"is_corresponding":false},{"id":1593066,"name":"Isabelle Kuan","orcid":null,"position":5,"is_corresponding":false},{"id":629764,"name":"Sant P. Chawla","orcid":"0000-0002-9522-6744","position":6,"is_corresponding":false},{"id":1264174,"name":"Thomas M. Polasek","orcid":"0000-0003-1008-5223","position":7,"is_corresponding":false},{"id":1593069,"name":"Jason Lickliter","orcid":null,"position":8,"is_corresponding":false},{"id":1469972,"name":"Philip J. Ryan","orcid":"0000-0002-4113-6751","position":9,"is_corresponding":false},{"id":1252804,"name":"Richard T. 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We developed a strategy to extend the rIL-12 T<jats:sub>½</jats:sub> that depends on binding albumin <jats:italic>in vivo</jats:italic> to target tumor tissue, using single-chain rIL-12 linked to a fully human albumin binding (F<jats:sub>H</jats:sub>AB) domain (SON-1010). After initiating a dose-escalation trial in patients with cancer (SB101), a randomized, double-blind, placebo-controlled, single-ascending dose (SAD) phase 1 trial in healthy volunteers (SB102) was conducted.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>SB102 (NCT05408572) focused on safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) endpoints. SON-1010 at 50-300 ng/kg or placebo administered subcutaneously on day 1 was studied at a ratio of 6:2, starting with two sentinels; participants were followed through day 29. Safety was reviewed after day 22, before enrolling the next cohort. A non-compartmental analysis of PK was performed and correlations with the PD results were explored, along with a comparison of the SON-1010 PK profile in SB101.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Participants receiving SON-1010 at 100 ng/kg or higher tolerated the injection but generally experienced more treatment-emergent adverse effects (TEAEs) than those receiving the lowest dose. All TEAEs were transient and no other dose relationship was noted. As expected with rIL-12, initial decreases in neutrophils and lymphocytes returned to baseline by days 9-11. PK analysis showed two-compartment elimination in SB102 with mean T<jats:sub>½</jats:sub> of 104 h, compared with one-compartment elimination in SB101, which correlated with prolonged but controlled and dose-related increases in interferon-gamma (IFNγ). There was no evidence of cytokine release syndrome based on minimal participant symptoms and responses observed with other cytokines.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>SON-1010, a novel presentation for rIL-12, was safe and well-tolerated in healthy volunteers up to 300 ng/kg. Its extended half-life leads to a prolonged but controlled IFNγ response, which may be important for tumor control in patients.</jats:p></jats:sec><jats:sec><jats:title>Clinical trial registration</jats:title><jats:p><jats:uri>https://clinicaltrials.gov/study/NCT05408572</jats:uri>, identifier NCT05408572.</jats:p></jats:sec>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"38487528","pmcid":null,"openalex_id":null,"authors":[],"funders":[],"total_grants":0,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1362775/pdf","host_type":"publisher"},{"url":"https://www.frontiersin.org/articles/10.3389/fimmu.2024.1362775/full","host_type":"publisher"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10937388/pdf/fimmu-15-1362775.pdf","host_type":"repository"}],"fields_of_study":[],"mesh_terms":["Animals","Humans","Mice","Neoplasms","Albumins","Recombinant Proteins","Interleukin-2","Interleukin-12","Cytokines","Interferon-gamma","Tumor Microenvironment","Healthy Volunteers"],"keywords":["Immunotherapy","Albumin","Ovarian cancer","Healthy Volunteers","Advanced Solid Tumors","Fully Human Albumin Binding (Fhab) Domain","Son-1010","Recombinant Il-12"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"nct"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-03T02:22:40.441408Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}