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.
SON-1010
advanced solid tumors
albumin
fully human albumin binding (FHAB) domain
healthy volunteers
immunotherapy
ovarian cancer
recombinant IL-12
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2024
2024
Historique:
received:
29
12
2023
accepted:
09
02
2024
medline:
18
3
2024
pubmed:
15
3
2024
entrez:
15
3
2024
Statut:
epublish
Résumé
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 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. 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 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. https://clinicaltrials.gov/study/NCT05408572, identifier NCT05408572.
Sections du résumé
Background
UNASSIGNED
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
Methods
UNASSIGNED
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.
Results
UNASSIGNED
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
Conclusion
UNASSIGNED
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.
Clinical trial registration
UNASSIGNED
https://clinicaltrials.gov/study/NCT05408572, identifier NCT05408572.
Identifiants
pubmed: 38487528
doi: 10.3389/fimmu.2024.1362775
pmc: PMC10937388
doi:
Substances chimiques
Interleukin-12
187348-17-0
Cytokines
0
Interferon-gamma
82115-62-6
Interleukin-2
0
Recombinant Proteins
0
Albumins
0
Banques de données
ClinicalTrials.gov
['NCT05408572']
Types de publication
Randomized Controlled Trial
Clinical Trial, Phase I
Case Reports
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1362775Informations de copyright
Copyright © 2024 Kenney, Cini, Dexter, DaFonseca, Bingham, Kuan, Chawla, Polasek, Lickliter and Ryan.
Déclaration de conflit d'intérêts
RK, JC, SD, and MD were employed by and have stock in Sonnet BioTherapeutics. JB and IK were employed by Momentum Metrix, a Sonnet consultant. SPC was employed by the Sarcoma Center and conducted the SB101 clinical study under contract with Sonnet. TP was employed by InClin, the Contract Research Organization responsible for the study. JL and PR were employed by the Nucleus Network and conducted the SB102 clinical study under contract with Sonnet. This study received funding from Sonnet BioTherapeutics. The Sonnet team was involved in the design and oversaw the conduct of the trial.
Références
Gastroenterol Hepatol (N Y). 2019 May;15(5):255-265
pubmed: 31360139
Blood. 1997 Oct 1;90(7):2541-8
pubmed: 9326219
Front Med (Lausanne). 2021 Sep 16;8:727987
pubmed: 34604264
J Immunother Cancer. 2019 Nov 15;7(1):305
pubmed: 31730010
Nat Commun. 2016 Nov 28;7:13466
pubmed: 27892456
Exp Hematol Oncol. 2014 Apr 11;3(1):11
pubmed: 24725395
Cold Spring Harb Perspect Biol. 2018 Dec 3;10(12):
pubmed: 29101107
Clin Transl Sci. 2019 Jan;12(1):6-19
pubmed: 30048046
Cytokine Growth Factor Rev. 2002 Apr;13(2):155-68
pubmed: 11900991
Adv Exp Med Biol. 2016;941:117-138
pubmed: 27734411
Front Immunol. 2020 Oct 15;11:575597
pubmed: 33178203
Eur J Immunol. 1996 Jun;26(6):1335-41
pubmed: 8647214
Front Immunol. 2018 Jan 05;8:1825
pubmed: 29354116
Cancers (Basel). 2022 Nov 14;14(22):
pubmed: 36428682
Cell Immunol. 1994 Jul;156(2):480-92
pubmed: 7912999
J Transl Med. 2009 Jan 14;7:5
pubmed: 19144161
Clin Cancer Res. 1998 Jan;4(1):75-85
pubmed: 9516955
Cancer Immunol Immunother. 1985;20(3):193-7
pubmed: 3933818
Curr Protoc Immunol. 2001 May;Chapter 20:Unit 20.2
pubmed: 18432775
J Immunol. 2010 Feb 15;184(4):1858-66
pubmed: 20061409
Clin Cancer Res. 2018 Jun 15;24(12):2716-2718
pubmed: 29549160
Cell Death Differ. 2015 Feb;22(2):237-46
pubmed: 25190142
J Transl Med. 2018 Dec 4;16(1):336
pubmed: 30509294
Sci Immunol. 2022 Jan 07;7(67):eabi6899
pubmed: 34995098
J Exp Med. 1993 Oct 1;178(4):1223-30
pubmed: 8104230
Science. 1997 Nov 28;278(5343):1623-6
pubmed: 9374462
Science. 1993 Apr 23;260(5107):547-9
pubmed: 8097338
Clin Cancer Res. 1997 Mar;3(3):409-17
pubmed: 9815699
J Immunother Cancer. 2023 May;11(5):
pubmed: 37236636
Cancers (Basel). 2021 Sep 03;13(17):
pubmed: 34503248
Front Immunol. 2023 Dec 20;14:1326927
pubmed: 38250068
Cancers (Basel). 2021 Jan 06;13(2):
pubmed: 33418929
J Natl Cancer Inst. 1995 Apr 19;87(8):581-6
pubmed: 7538593
Biol Blood Marrow Transplant. 2019 Apr;25(4):625-638
pubmed: 30592986
Electrophoresis. 2008 Nov;29(21):4368-76
pubmed: 19016565
Curr Opin Biotechnol. 2009 Dec;20(6):722-9
pubmed: 19896825
Adv Drug Deliv Rev. 2018 May;130:73-89
pubmed: 30012492
J Natl Cancer Inst. 1997 Jul 16;89(14):1049-58
pubmed: 9230887
Toxicol Pathol. 1999 Jan-Feb;27(1):58-63
pubmed: 10367675
Immunity. 1998 Jul;9(1):25-34
pubmed: 9697833
Clin Cancer Res. 2019 Jan 1;25(1):99-109
pubmed: 30131389
Chonnam Med J. 2019 Jan;55(1):31-39
pubmed: 30740338