In vivo biological results of the association between interleukin-2 and interleukin-3 in the immunotherapy of cancer

The biologic in vivo effects of recombinant human interleukin-3 (rhIL-3) were assessed in a phase I clinical study of 30 patients with advanced malignancy. On day 1 rhIL-3 was administered by a single intravenous (IV) bolus injection, followed by subcutaneous (SC) injections once daily from day 2 to 15; at least three patients were treated at each dose level (60, 125, 250, and 500 micrograms/m2). A transient decrease of eosinophil and monocyte counts was observed immediately after IV injection of rhIL-3, whereas the neutrophil count remained unaffected. Total WBC counts and neutrophil counts increased dose dependently up to threefold, whereas a 10-fold to 50-fold rise was observed in levels of circulating eosinophils and basophils. Platelet counts increased up to twofold. Patients developed moderate increases of serum levels of soluble interleukin-2 receptors, beta 2-microglobin, and immunoglobulin M (IgM), and of the acute phase reactants, C-reactive protein (CRP), fibrinogen, and haptoglobin. An increase in interleukin-6 (IL-6) serum levels was detected in patients treated by IV bolus rhIL-3. The serum half-life of IV injected rhIL-3 was 20 +/- 3 minutes; after SC administration, 210 +/- 15 minutes. Administration of rhIL-3 was generally well tolerated, with mild fever, headache, and local reactions at the injection site being the most frequent side effects. The primary course of the underlying malignant diseases was not significantly altered by administration of rhIL-3. The results indicate that rhIL-3 acts in vivo as a multilineage hematopoietic growth factor and a weak inflammatory mediator that may be used successfully to improve states of hematopoietic failure.

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Effect of in vivo administration of the carcinogen benzo(a)pyrene on interleukin-2 and interleukin-3 production

International Journal of Immunopharmacology ◽

10.1016/0192-0561(87)90055-5 ◽

1987 ◽

Vol 9 (3) ◽

pp. 307-312 ◽

Cited By ~ 23

Author(s):

Mark Lyte ◽

Robert H. Blanton ◽

Michael J. Myers ◽

Peter H. Bick

Keyword(s):

Interleukin 2 ◽

Interleukin 3 ◽

In Vivo Administration

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Spontaneous In Vivo Gene Transcription of Interleukin-2, Interleukin-3, Interleukin-4, Interleukin-6, Interferon-Gamma, Interleukin-2 Receptor (CD25) and Proto-Oncogene c-myc by Rheumatoid Synovial T Lymphocytes

Scandinavian Journal of Immunology ◽

10.1111/j.1365-3083.1992.tb03148.x ◽

1992 ◽

Vol 36 (6) ◽

pp. 865-874 ◽

Cited By ~ 16

Author(s):

K. WAALEN ◽

M. SIOUD ◽

J. B. NATVIG ◽

O. FORRE

Keyword(s):

T Lymphocytes ◽

Interferon Gamma ◽

Gene Transcription ◽

Interleukin 6 ◽

Interleukin 2 ◽

Interleukin 4 ◽

Interleukin 3 ◽

Interleukin 2 Receptor

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Generation of low-toxicity interleukin-2 fusion proteins devoid of vasopermeability activity

Blood ◽

10.1182/blood-2002-10-3089 ◽

2003 ◽

Vol 101 (12) ◽

pp. 4853-4861 ◽

Cited By ~ 28

Author(s):

Peisheng Hu ◽

Myra Mizokami ◽

Gina Ruoff ◽

Leslie A. Khawli ◽

Alan L. Epstein

Keyword(s):

Fusion Proteins ◽

Single Point ◽

Interleukin 2 ◽

Point Mutations ◽

Lymphoid Malignancies ◽

Immunotherapy Of Cancer ◽

Immunocompetent Mice ◽

Undesirable Property ◽

Proliferation Assays

AbstractBecause of its key role in immunity, interleukin-2 (IL-2) has been studied extensively for the adoptive immunotherapy of cancer. Although systemic administration of IL-2 has been shown to stimulate antitumor responses in vivo, its efficacy in the clinic has been limited by the development of serious side effects, including the induction of vascular leak syndrome. Previously, we have identified a small peptide fragment of IL-2 that was found to contain the entire vasopermeability activity of the cytokine. The identification of the location of this potentially undesirable property of IL-2 enabled us to focus on the generation of mutant derivatives that might be lacking vasopermeability activity but that retain cytokine functionality. In addition to this discovery, our laboratory has constructed monoclonal antibody/IL-2 fusion proteins that can target this potent cytokine directly to tumor for the immunotherapy of both solid and lymphoid malignancies. Using this fusion protein technology, we have constructed a series of point mutations in the newly identified vasopermeability region of IL-2 for the purpose of deleting this activity. Fusion proteins showing reduced or deleted vasopermeability activity were then tested for their cytokine potency by several methods, including their binding to IL-2 receptors, T-cell proliferation assays, the induction of secondary cytokines, dose-escalating toxicity, and finally their ability to treat established solid tumors in syngeneic immunocompetent mice. The results of these studies clearly show that the vasopermeability activity of IL-2 can be substantially deleted by single point mutations such as Arg38Trp without grossly affecting the immune function of the cytokine.

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A bispecific antibody agonist of the IL-2 heterodimeric receptor preferentially promotes in vivo expansion of CD8 and NK cells

Scientific Reports ◽

10.1038/s41598-021-90096-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Katherine E. Harris ◽

Kyle J. Lorentsen ◽

Harbani K. Malik-Chaudhry ◽

Kaitlyn Loughlin ◽

Harish Medlari Basappa ◽

...

Keyword(s):

T Cells ◽

Nk Cells ◽

Bispecific Antibody ◽

T Regulatory Cells ◽

Tumor Regression ◽

Interleukin 2 ◽

In Vivo Studies ◽

Preferential Binding

AbstractThe use of recombinant interleukin-2 (IL-2) as a therapeutic protein has been limited by significant toxicities despite its demonstrated ability to induce durable tumor-regression in cancer patients. The adverse events and limited efficacy of IL-2 treatment are due to the preferential binding of IL-2 to cells that express the high-affinity, trimeric receptor, IL-2Rαβγ such as endothelial cells and T-regulatory cells, respectively. Here, we describe a novel bispecific heavy-chain only antibody which binds to and activates signaling through the heterodimeric IL-2Rβγ receptor complex that is expressed on resting T-cells and NK cells. By avoiding binding to IL-2Rα, this molecule circumvents the preferential T-reg activation of native IL-2, while maintaining the robust stimulatory effects on T-cells and NK-cells in vitro. In vivo studies in both mice and cynomolgus monkeys confirm the molecule’s in vivo biological activity, extended pharmacodynamics due to the Fc portion of the molecule, and enhanced safety profile. Together, these results demonstrate that the bispecific antibody is a safe and effective IL-2R agonist that harnesses the benefits of the IL-2 signaling pathway as a potential anti-cancer therapy.

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Regulation of pim and myb mRNA accumulation by interleukin 2 and interleukin 3 in murine hematopoietic cell lines.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)77880-6 ◽

1988 ◽

Vol 263 (33) ◽

pp. 17615-17620

Author(s):

F Dautry ◽

D Weil ◽

J Yu ◽

A Dautry-Varsat

Keyword(s):

Cell Lines ◽

Interleukin 2 ◽

Hematopoietic Cell ◽

Mrna Accumulation ◽

Interleukin 3 ◽

Hematopoietic Cell Lines

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A cytokine receptor-masked IL2 prodrug selectively activates tumor-infiltrating lymphocytes for potent antitumor therapy

Nature Communications ◽

10.1038/s41467-021-22980-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Eric J. Hsu ◽

Xuezhi Cao ◽

Benjamin Moon ◽

Joonbeom Bae ◽

Zhichen Sun ◽

...

Keyword(s):

Metastatic Cancer ◽

Interleukin 2 ◽

Tumor Infiltrating Lymphocytes ◽

Immune Checkpoint Blockade ◽

Targeting Therapy ◽

Protease Substrate ◽

Reduced Toxicity ◽

Infiltrating Lymphocytes ◽

Receptor Beta

AbstractAs a potent lymphocyte activator, interleukin-2 (IL-2) is an FDA-approved treatment for multiple metastatic cancers. However, its clinical use is limited by short half-life, low potency, and severe in vivo toxicity. Current IL-2 engineering strategies exhibit evidence of peripheral cytotoxicity. Here, we address these issues by engineering an IL-2 prodrug (ProIL2). We mask the activity of a CD8 T cell-preferential IL-2 mutein/Fc fusion protein with IL2 receptor beta linked to a tumor-associated protease substrate. ProIL2 restores activity after cleavage by tumor-associated enzymes, and preferentially activates inside tumors, where it expands antigen-specific CD8 T cells. This significantly reduces IL-2 toxicity and mortality without compromising antitumor efficacy. ProIL2 also overcomes resistance of cancers to immune checkpoint blockade. Lastly, neoadjuvant ProIL2 treatment can eliminate metastatic cancer through an abscopal effect. Taken together, our approach presents an effective tumor targeting therapy with reduced toxicity.

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