Innate Pharma SA's investigational tetra-specific NK cell engager, IPH6501, is emerging as a potential therapeutic option for relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL). Preclinical data suggests that IPH6501 may offer improved efficacy and reduced toxicity compared to existing T cell-based immunotherapies.
IPH6501: A Novel Approach to B-NHL Therapy
IPH6501, developed using Innate’s ANKET (Antibody-based NK cell Engager Therapeutics) platform, is designed to simultaneously engage activating receptors (NKp46 and CD16) on natural killer (NK) cells, target the tumor-associated antigen CD20 on B cells, and stimulate an interleukin-2 receptor (via an IL-2 variant, IL-2v). This multi-pronged approach aims to enhance NK cell activation and proliferation while minimizing off-target effects.
Preclinical Efficacy and Safety
Preclinical studies have demonstrated that IPH6501 effectively binds to both cancerous B cells and NK cells, triggering the innate immune system to target malignant cells. In mouse models and non-human primates, IPH6501 exhibited superior anti-tumor activity and reduced toxicity compared to CD20-targeting T cell engagers (TCEs). Specifically, the molecule was designed to include an IL-2 variant that could trigger NK cell proliferation without activating regulatory T cells (Tregs) and did not show IL-2-related side effects.
Olivier Demaria and colleagues also produced a variant of the molecule, named CD20-NKCE-IL2v, with a key change in one domain to enable testing in mice. In vitro studies confirmed that IPH6501 promotes NK cell activation. In vivo, CD20-NKCE-IL2v and IPH6501 elicited NK cell expansion and migration to tumor sites in mouse models and non-human primates, respectively. IPH6501 also induced proliferation and efficient anti-tumour activity in NK cell samples from relapsed or unresponsive B-NHL patients.
Broad Therapeutic Potential
Notably, IPH6501 demonstrated the ability to activate NK cells to target CD20-negative tumor cells, suggesting potential utility against a broader range of lymphomas. Furthermore, it showed strong anti-tumor efficacy in a tumor model resistant to rituximab and obinutuzumab, as well as post-CAR-T cell therapy.
Clinical Development
IPH6501 is currently being evaluated in a Phase I/II dose-escalation trial in patients with relapsed or unresponsive B-NHL. The study design was presented at the ASCO conference this year.
