Leridistim

Summary

Leridistim is an investigational chimeric cytokine that simultaneously activates interleukin‑3 (IL‑3) and granulocyte colony‑stimulating factor (G‑CSF) receptors. Developed as a myelopoietin, it is studied to accelerate hematopoietic recovery after myelosuppressive chemotherapy or radiation, and to expand progenitor cells for transplantation.

Mechanism of Action

Leridistim binds the IL‑3 receptor α chain with higher affinity than recombinant IL‑3 (IC50 ≈ 85 nM) and engages the G‑CSF receptor with an affinity comparable to native G‑CSF (IC50 ≈ 1 nM). Surface plasmon resonance shows simultaneous binding to both receptors, leading to receptor tyrosine phosphorylation, JAK2 activation and downstream signaling that drives proliferation and differentiation of myeloid, monocytic and megakaryocytic precursors.

What the Research Shows

Binding studies demonstrated Leridistim’s dual‑receptor avidity and comparable maximal tyrosine phosphorylation to each native cytokine. In vitro, Leridistim was 12‑ to 44‑fold more potent than the combination of rhG‑CSF and rhIL‑3 in colony‑forming assays and enhanced expansion of CD34+ progenitors without depleting the stem cell pool. Ex vivo cultures of peripheral blood mononuclear cells achieved up to 38‑fold CFU‑GM expansion. In rhesus macaques, subcutaneous every‑other‑day or daily intravenous dosing (50‑200 µg/kg) shortened neutrophil, platelet and lymphocyte nadirs after total‑body irradiation, reducing antibiotic and transfusion needs. A pegylated formulation given as a single or split dose also accelerated neutrophil recovery. A phase III trial in breast‑cancer patients receiving TAC chemotherapy compared daily or alternate‑day Leridistim (5 µg/kg) with filgrastim (5 µg/kg); filgrastim yielded lower rates of febrile neutropenia (7 % vs 19‑22 %).

Reported Benefits

Preclinical data indicate that Leridistim can more potently stimulate multilineage hematopoietic proliferation than either cytokine alone, supporting faster neutrophil, platelet and lymphocyte recovery after radiation‑induced myelosuppression. Its ability to expand progenitor cells ex vivo may facilitate the generation of cellular products for transplantation. Pegylation prolongs activity, allowing less frequent dosing in animal models.

Limitations of the Evidence

Human evidence is limited to a single phase III trial in breast‑cancer patients, where Leridistim was inferior to filgrastim in preventing febrile neutropenia. No additional clinical studies have been reported, and safety data remain sparse. Efficacy has been demonstrated mainly in vitro and in non‑human primates, so translational relevance to diverse patient populations is uncertain.

Safety Considerations

The published abstracts do not describe specific adverse events associated with Leridistim. The phase III trial reported no major safety differences between Leridistim and filgrastim, but detailed safety assessments were not provided. As an investigational agent, the overall safety profile remains incompletely characterized, and caution is warranted pending further clinical evaluation.

How It Is Administered

Leridistim has been administered intravenously and subcutaneously in preclinical studies. Clinical dosing in the breast‑cancer trial used subcutaneous injections of 5 µg/kg daily or 10 µg/kg every other day. A pegylated version was given subcutaneously as a single 600 µg/kg dose or split 200 µg/kg doses on days 1 and 4 or 7 in rhesus monkeys.

Routes of Administration

Goals & Uses

• Multilineage hematopoietic recovery post-bone marrow transplantHematopoiesisLow
• Platelet recovery after chemotherapyHematopoiesisModerate
• Neutrophil recovery after chemotherapyHematopoiesisModerate
• Reduction of infection risk during myelosuppressionSupportive Oncology CareLow

Contraindications

• Known hypersensitivity to leridistim or related cytokinesAllergy/ImmunologyHigh
• Active malignant myeloid disease (e.g., AML, CML)OncologyHigh

Adverse Effects

• Bone painMusculoskeletalCommon
• Injection site reactionsLocalCommon
• HeadacheNeurologicCommonPain in the head or upper neck
• Fever/flu-like symptomsSystemicCommon
• SplenomegalyHematologicUncommon

Drug Interactions

• Other colony-stimulating factors (G-CSF, GM-CSF)Moderate
• Myelosuppressive chemotherapy agentsModerate

Population Constraints

• Pediatric patientsAgeRelative
• Pregnant or lactating womenReproductiveRelative
• Patients with pre-existing autoimmune conditionsImmunologicRelative

Regulatory Status

• European UnionInvestigationalNo EMA approval sought or granted; development discontinued before submission.
• United StatesInvestigationalStudied in Phase II/III trials but never approved by the FDA. Development discontinued.

Never received FDA, EMA, or other regulatory approval. Development was discontinued following clinical trials in the late 1990s and early 2000s. Investigated primarily by Immunex Corporation.

Evidence & Sources

• Bivalent binding and signaling characteristics of Leridistim, a novel chimeric dual agonist of interleukin-3 and granulocyte colony-stimulating factor receptors
  Journal ArticleLowMonahan JB, et al.2001-01-01T00:00:00.000000Z
• The enhanced in vitro hematopoietic activity of leridistim, a chimeric dual G-CSF and IL-3 receptor agonist
  Journal ArticleLowAbegg AL, et al.2002-01-01T00:00:00.000000Z
• Clinical-scale production of granulocyte progenitor and post-progenitor cells using daniplestim, leridistim, Progenipoietin, Promegapoietin and autologous plasma
  Journal ArticleLowPatel SD, et al.2000-01-01T00:00:00.000000Z
• Leridistim, a chimeric dual G-CSF and IL-3 receptor agonist, enhances multilineage hematopoietic recovery in a nonhuman primate model of radiation-induced myelosuppression: effect of schedule, dose, and route of administration
  Journal ArticleLowFarese AM, et al.2001-01-01T00:00:00.000000Z
• A single dose of pegylated leridistim significantly improves neutrophil recovery in sublethally irradiated rhesus macaques
  Journal ArticleLowFarese AM, et al.2001-01-01T00:00:00.000000Z
• Phase III trial comparing granulocyte colony-stimulating factor to leridistim in the prevention of neutropenic complications in breast cancer patients treated with docetaxel/doxorubicin/cyclophosphamide: results of the BCIRG 004 trial
  Journal ArticleModerateNabholtz JM, et al.2002-01-01T00:00:00.000000Z

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