Investigational Drug
PDS0301
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Overview
PDS0301 (also known as M9241, NHS‑IL12; more recently referred to by PDS as PDS01ADC) is a tumor‑targeted interleukin‑12 (IL‑12) immunocytokine administered subcutaneously. It was originally developed by Merck KGaA/EMD Serono and later licensed to PDS Biotechnology. Early phase trials have evaluated it alone and in combinations (e.g., with avelumab or with a therapeutic HPV vaccine plus bintrafusp alfa) across advanced solid tumors, including HPV‑associated cancers and urothelial carcinoma. (globenewswire.com)
Mechanism of action
- Construct: Two IL‑12 p70 heterodimers are fused to the C‑termini of the human IgG1 antibody NHS76. NHS76 binds exposed DNA/histone complexes abundant in necrotic regions of tumors, concentrating IL‑12 in the tumor microenvironment and improving pharmacokinetics versus recombinant IL‑12. (aacrjournals.org)
- Immunologic effects: Local IL‑12 promotes Th1 immunity, CD8+ T‑cell and NK‑cell activation, high IFN‑γ production, and reduction of immunosuppressive myeloid cells; IFN‑γ‑driven PD‑L1 upregulation provides a rationale for combinations with PD‑(L)1 blockade. (pubmed.ncbi.nlm.nih.gov)
Clinical experience
Phase I monotherapy (first‑in‑human): In a dose‑escalation study in metastatic solid tumors (n=59), subcutaneous NHS‑IL12 had a maximum tolerated dose of 16.8 µg/kg every 4 weeks; common treatment‑related adverse events included transient lymphopenia, transaminase elevations, and flu‑like symptoms. Pharmacodynamic increases in IFN‑γ and IL‑10 were observed. (pubmed.ncbi.nlm.nih.gov)
Phase Ib combination with avelumab (JAVELIN IL‑12; NCT02994953): In dose escalation (n=36), the regimen was tolerated and two patients with advanced bladder cancer achieved prolonged complete responses; the urothelial carcinoma dose‑expansion cohort (n=16) recorded no objective responses and did not proceed to randomized stage 2. Recommended phase II dosing used M9241 16.8 µg/kg Q4W plus avelumab 800 mg (induction weekly ×12 then Q2W). (pubmed.ncbi.nlm.nih.gov)
Phase 1/2 NCI‑led triple combination in HPV‑associated cancers (PDS0101 vaccine + PDS0301/PDS01ADC + bintrafusp alfa; single‑center, nonrandomized; n=50; enrollment June 2020–July 2022; data cutoff May 13, 2024):
- Objective response rate (primary in ICB‑naive): 35.7% (5/14; 95% CI, 12.8–64.9); in HPV‑16–positive, ICB‑naive patients: 62.5% (5/8; 95% CI, 24.5–91.5).
- ICB‑resistant cohort: ORR 16.7% (6/36).
- Median overall survival: 42.4 months in ICB‑naive (95% CI, 8.3 months–NE) and 15.8 months in ICB‑resistant (95% CI, 9.0–21.3).
These results support further evaluation of the combination. (jamanetwork.com)
Additional clinical exploration: The NCI reported preliminary safety/immune data for combining PDS01ADC with docetaxel in metastatic prostate cancer at Cytokines 2023 (abstract presentation). (pdsbiotech.com)
Efficacy
- Monotherapy: The first‑in‑human study established biologic activity and an MTD but was not powered for efficacy endpoints. (pubmed.ncbi.nlm.nih.gov)
- Combination with PD‑L1 blockade (avelumab): Evidence of durable complete responses in dose escalation, but no confirmed objective responses in the urothelial carcinoma expansion cohort. (pubmed.ncbi.nlm.nih.gov)
- Triple combination in HPV‑associated cancers: Clinically meaningful activity, particularly in HPV‑16–positive, ICB‑naive patients (ORR 62.5%); responses also observed in ICB‑resistant disease (ORR 16.7%). (jamanetwork.com)
Safety
- Characteristic toxicities align with IL‑12 biology (flu‑like symptoms, transient cytopenias, transaminase elevations); in the phase I monotherapy study, grade ≥3 TRAEs were mostly laboratory abnormalities and transient, with MTD 16.8 µg/kg Q4W. (pubmed.ncbi.nlm.nih.gov)
- In JAVELIN IL‑12, combination treatment‑related AEs occurred in 93.8% (any grade) and 50% (grade ≥3) in the UC expansion, with no treatment‑related deaths; one DLT (grade 3 autoimmune hepatitis) occurred in dose escalation. (pubmed.ncbi.nlm.nih.gov)
- In the 50‑patient triple‑therapy trial, any‑grade treatment‑related AEs occurred in all patients and grade 3–4 in 52%; mucosal bleeding events of special interest were reported, with no treatment‑related deaths. (jamanetwork.com)
Notes on nomenclature
PDS0301/M9241/NHS‑IL12 has been rebranded by PDS Biotechnology as PDS01ADC; corporate filings and pipeline materials indicate these are the same investigational agent. (annual-statements.com)
Further reading
- First‑in‑human NHS‑IL12 monotherapy (phase I): Clinical Cancer Research, 2019. (pubmed.ncbi.nlm.nih.gov)
- Preclinical rationale and construct details for NHS‑IL12 and PD‑L1 combinations: Clinical Cancer Research, 2017; Oncotarget, 2017. (aacrjournals.org)
- JAVELIN IL‑12 (M9241 + avelumab) phase Ib results: BMJ/JITC 2023; Annals of Oncology conference report. (pubmed.ncbi.nlm.nih.gov)
- HPV‑associated cancers (PDS0101 + PDS01ADC/PDS0301 + bintrafusp alfa) phase 1/2 trial: JAMA Oncology, 2025. (jamanetwork.com)
- Mechanistic reviews of NHS‑IL12 immunobiology: Frontiers in Immunology, 2021; Frontiers in Immunology, 2024. (pubmed.ncbi.nlm.nih.gov)
Disclosure: PDS’s corporate materials and filings provide additional context on naming and licensing but should be interpreted alongside peer‑reviewed data. (globenewswire.com)
Last updated: Oct 2025
Active trials using PDS0301
Found 5 active trials using this drug:
HealthScout AI summary: Men with PSMA PET–positive biochemical recurrence after definitive local therapy, no visceral/bone mets, testosterone >100 ng/dL, and PSA DT <12 months are randomized to short-course enzalutamide without ADT versus enzalutamide plus PDS01ADC (NHS-IL12), an IL‑12 immunocytokine that targets exposed histones in necrotic tumor regions to deliver IL‑12 and stimulate NK/T‑cell activity. Designed to test whether adding PDS01ADC prolongs PSA control; retreatment with enzalutamide alone allowed upon PSA return to baseline.
ClinicalTrials.gov ID: NCT06096870
HealthScout AI summary: This trial enrolls adults with liver-only or liver-dominant metastatic colorectal cancer, intrahepatic cholangiocarcinoma, or adrenocortical carcinoma who have progressed on prior chemotherapy, and treats them with hepatic artery infusion pump (HAIP) floxuridine-based chemotherapy plus standard systemic therapy and PDS01ADC, an investigational IL-12–based immunocytokine targeting necrotic tumor regions to enhance local immune activation. Cohorts are separated by tumor type.
ClinicalTrials.gov ID: NCT05286814
HealthScout AI summary: Adults with metastatic prostate cancer: mCSPC within ~4 months of starting ADT (high-volume for expansion) receive ADT + docetaxel + abiraterone/prednisone, with addition of M9241 (NHS‑IL12), a tumor-targeted IL‑12 immunocytokine that binds exposed histones to deliver IL‑12 to the tumor microenvironment. mCRPC patients previously treated with a modern ARSI (but not progressed on prior mCSPC docetaxel) receive docetaxel/prednisone plus M9241 from cycle 2 onward.
ClinicalTrials.gov ID: NCT04633252
HealthScout AI summary: Adults with metastatic non‑prostate genitourinary cancers (e.g., urothelial, renal cell, germ cell) receive bintrafusp alfa (anti–PD‑L1/TGF‑β trap) plus PDS01ADC/NHS‑IL12 (tumor‑targeted IL‑12 immunocytokine), with or without SBRT to up to four lesions, to assess safety and dosing. Prior systemic therapy and checkpoint inhibitors are allowed; SBRT cohorts require at least one irradiable lesion and one non‑irradiated measurable lesion.
ClinicalTrials.gov ID: NCT04235777
HealthScout AI summary: Adults with biopsy‑proven advanced Kaposi sarcoma (HIV+ on stable ART or HIV−), ECOG 0–2, and ≥5 measurable cutaneous lesions; prior systemic therapy allowed. Investigational IL‑12–targeted immunocytokine PDS01ADC (NHS‑IL12) is given subcutaneously every 28 days as monotherapy or combined with bintrafusp alfa (M7824), a bifunctional PD‑L1 blocker/TGF‑β trap given IV q2w.
ClinicalTrials.gov ID: NCT04303117
