ANKET® (Antibody-based NK cell Engager Therapeutics) is Innate’s proprietary platform for developing next-generation, multi-specific NK cell engagers to treat certain types of cancer.
ANKET® technology engages NK cells by simultaneously targeting several activating receptors, and kills tumor cells by targeting a tumor antigen. Innate Pharma has developed two generations of NK Cell Engagers:
• The tri-specific molecules target both CD16 (a receptor that activates the anti-tumor activity of NK cells) and NKp46 (another activating receptor, capable of stimulating and reinforcing, in synergy with CD16 activation, the anti-tumor activity of NK cells. This receptor is the most specific for NK cells, and its expression is maintained in NK cells infiltrating solid tumors).
• Tetra-specific molecules also target the interleukin-2 receptor (via a variant IL-2, IL-2v) to promote NK cell proliferation and thus amplify their capacity for anti-tumor activity.
Multispecific NK Cell Engagers demonstrate better anti-tumor efficacy than approved reference antibodies in preclinical models.
Learn more about targeting NK cells and their important role in activating an anti-tumor response.
Innate’s pipeline includes four drug candidates born from the ANKET® platform:
- Three under collaboration with Sanofi, including IPH6101/SAR443579 (CD123) currently in Phase 1/2 in various blood cancers, IPH6401/SAR445514 -BCMA) currently in Phase 1/2 in multiple myeloma, IPH62 (B7-H3)
- IPH6501 (proprietary) in Phase 1/2 multicenter trial, investigating the safety and tolerability of IPH6501 in patients with Relapsed and/or Refractory CD20-expressing B-cell Non-Hodgkin’s Lymphoma (NHL)
NKp46, an activating receptor, plays a crucial role in ANKET's induction of anti-cancer effector functions in NK cells. It can be co-engaged with other receptors, such as CD16, to enhance NK cell activity. NKp46 is the most specific marker for human NK cells, giving ANKETs enhanced specificity for these cells. Unlike most activating receptors, NKp46 expression is conserved on tumor-infiltrating NK cells, supporting the rationale for its involvement in promoting an effective anti-tumor response and overcoming some of the limitations of ADCC (antibody-dependent cell cytotoxicity). The ANKET activity data obtained in preclinical experiments, combined with the advantageous safety profile observed in preclinical and early clinical studies, position these molecules as a promising alternative to new immunotherapy strategies, such as CAR-T and bispecific T-cell engagers.
Interleukin-2 (IL-2) is a cytokine that plays a key role in the activation and proliferation of NK cells. A variant IL-2 (IL-2v) was designed to activate these cells while limiting the activation of regulatory T cells (Tregs). Integrating an IL-2v arm into tetra-specific ANKET molecules not only engages NKp46 and CD16 receptors, but also stimulates NK cell proliferation, thereby increasing their numbers and anti-tumor efficacy. In vivo studies in non-human primates and in murine tumor models revealed that tetra-specific ANKETs, at well-tolerated doses, significantly stimulated peripheral NK cell proliferation, promoted their accumulation at the tumor site, and effectively eradicated targeted cells in blood and tissue.
In addition, IL-2v-equipped ANKETs stimulate the expression of several activator receptors such as NKG2D on NK cells, facilitating the recognition and spontaneous elimination of tumor cells not presenting the antigen targeted by the ANKET. This additional mechanism could enhance efficacy against tumors with heterogeneous expression of the target antigen, reinforcing the potential of ANKETs in complex tumor environments.
Gauthier, et al, Multifunctional Natural Killer Cell Engagers Targeting NKp46 Trigger Protective Tumor Immunity. Cell 2019. 177: 1701-1713 e1716.
Gauthier et al, 2023. Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123 Nature Biotechnology
Demaria et al, 2022. Antitumor immunity induced by antibody-based natural killer cell engager therapeutics armed with not-alpha IL-2 variant Cell Reports Medicine
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