Background:
Despite the progress made in cancer therapy with monoclonal antibodies, such as the CD20 antibody rituximab, there remains a pressing need to optimize the ability of such antibodies to induce antibody-dependent cellular cytotoxicity (ADCC), which determines therapeutic efficacy.
(Data source: Maloney DG. N Engl J Med. 2012)
The cytokine IL-15 stimulates the proliferation, activation, and cytolytic capacity of NK cells, but its short half-life, poor accumulation at tumor sites, and severe toxicity caused by nonspecific immune activation hinder its widespread clinical application.
(Data source: Nektar Therapeutics)
Recently, a German research team published their latest research results in Sci Transl Med: they constructed a CD19/CD20 antibody with an optimized Fc structure and an E46K mutant IL15 cytokine fusion, which mediated excellent NK cell immunity. Compared with the parental monoclonal antibody, the treatment of leukemia mouse models showed better tumor control, demonstrating a promising new immunotherapy method for B cell malignancies.
(Data source: Klein C, et al. Nat Rev Drug Discov. 2024)
Molecular design:
Using the glycoengineered CD20 monoclonal antibody (GA101/obinutuzumab) and CD19 monoclonal antibody (XmAb5574/MOR208, tafasitamab) (approved for the treatment of chronic lymphocytic leukemia and diffuse large B-cell lymphoma) antibody backbone with amino acid exchanges S239D and I332E (SDIE mutation modification, used to enhance antibody-mediated ADCC effect), the IL15 protein was fused to the C-terminus of the antibody heavy chain to generate the fusion molecule IC19. At the same time, the IL15 and IL-15Ra binding site E46K was mutated to lose its binding effect, and further modified into MIC19 to avoid unconditional activation of NK cells.
Proof of Concept:
Compared with the use of IL15 recombinant protein alone or in combination with monoclonal antibodies, the use of MIC19 molecules can deliver IL15 to NK cells in a targeted manner and reduce the adverse effects caused by off-target effects of recombinant IL15. In addition to antibody-mediated ADCC to enhance NK effector function, IL15 can also effectively stimulate the expansion and survival of NK cells.
Functional characterization:
In comparison with the parental mAb in in vitro cell killing assays, both MIC19 and MIC20 enhanced the lysis of tumor target cells.
Animals were adoptively transferred with human PBMCs and injected with equimolar doses of MIC19 and MIC20, either alone or in combination with the parental mAb and rIL15 and an isotype control. Repeated treatments on days 5, 7, and 9, followed by bioluminescence imaging of tumor growth over time, demonstrated that both MIC19 and MIC20 mediated enhanced anti-leukemic effects.
Summary:
Immunostimulatory cytokines such as IL-2 or IL-15 can effectively stimulate the anti-tumor reactivity of cytotoxic lymphocytes. Combining them with mAbs can enhance ADCC activity. While the use of IL-2 and IL-15 has yielded promising results in clinical trials, they are associated with numerous treatment-related adverse events, limiting the applicable dose. MIC fusions combine the advantages of Fc-optimized antibodies and IL-15 activity, inducing potent NK cell responses and proliferation against B-cell malignancies while minimizing nonspecific effects, benefiting from improved NK cell ADCC induction.
