Abstract
Successful immunotherapy of Hodgkin's disease is so far hampered by the striking unresponsiveness of lymphoma infiltrating immune cells. To mobilize both adoptive and innate immune cells for an anti-tumor attack we fused the pro-inflammatory cytokines IL2 and IL12 to an anti-CD30 scFv antibody in a dual cytokine fusion protein to accumulate both cytokines at the malignant CD30+ Hodgkin/Reed-Sternberg cells in the lymphoma lesion. The tumor-targeted IL12-IL2 fusion protein was superior in activating resting T cells to amplify and secrete pro-inflammatory cytokines compared to targeted IL2 or IL12 alone. NK cells were also activated by the dual cytokine protein to secrete IFN-γ and to lyse target cells. The tumor-targeted IL12-IL2, when applied by i.v. injection to immune-competent mice with established antigen-positive tumors, accumulated at the tumor site and induced tumor regression. Data demonstrate that simultaneous targeting of two cytokines in a spatial and temporal simultaneous fashion to pre-defined tissues is feasible by a dual-cytokine antibody fusion protein. In the case of IL12 and IL2, this produced superior anti-tumor efficacy implying the strategy to muster a broader immune cell response in the combat against cancer.
Highlights
Therapy of classical Hodgkin’s lymphoma and other CD30+ lymphomas has considerably improved during the last two decades [1]; the long-term toxicity of current regimens, is still strikingly high, providing a need for alternative strategies
Anti-CD30-antibody-cytokine fusion proteins with combined IL12-IL2 cytokine domains We generated a series of recombinant anti-CD30 antibodycytokine fusion proteins, each with the same anti-CD30 HRS3 single chain fragment of variable regions antibody for targeting CD30+ Hogdkin’s lymphoma cells, but with different cytokine domains (Fig. 1)
We addressed how various formats of anti-CD30 cytokine fusion proteins are affected by soluble CD30 in HRS3 single chain fragment of variable regions (scFv) antibody mediated binding to solid phase bound CD30
Summary
Therapy of classical Hodgkin’s lymphoma and other CD30+ lymphomas has considerably improved during the last two decades [1]; the long-term toxicity of current regimens, is still strikingly high, providing a need for alternative strategies. Cytokines which reverse the polarized immune response are thought to be good candidates to re-activate an anti-tumor immune response; antibody-targeted cytokines that accumulate in the lymphoma lesion are thought to be more efficacious than unmodified cytokines. This provides the rationale to target cytokines towards H/RS tumor cells by use of antibody-cytokine fusion proteins. Local re-activation of the immune response seems to be beneficial in the therapy of Hodgkin’s lymphoma since bi-specific antibody-mediated activation of NK cells along with T cells in the lymphoma lesion showed some therapeutic effect [12,13,14]. A recombinant bi-specific antibody targeting CD30 on Hodgkin’s lymphoma cells and the Fc c receptor (CD64) on monocytes triggers CD64 mediated effector functions [15]
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