IPH4102: first-in-class anti-KIR3DL2 cytotoxic mAb
About this program
IPH4102 is a first-in-class anti-KIR3DL2 humanized cytotoxic antibody (IgG1), designed to selectively destroy CTCL cancer cells.
KIR3DL2 is an inhibitory receptor of the KIR family, normally expressed on a fraction of normal NK cells but specifically expressed in all subtypes of the orphan indication of cutaneous T-cell lymphomas (CTCL). CTCL is a group of rare cutaneous lymphomas of T lymphocytes with poor prognosis and few therapeutic options at advanced stages.
IPH4102 selectively binds KIR3DL2 and has demonstrated a high level of efficacy in various pre-clinical models. It has been granted orphan drug designation in the European Union for the treatment of CTCL.
IPH4102 is currently in Phase I trial for the treatment of CTCL. Biomarker tools are developed in parallel to allow the monitoring of KIR3DL2 expression in patients.
IPH4102 is an anti-KIR3DL2 cytotoxic Mab
IPH4102 selectively binds KIR3DL2 and aims at depleting cancer cells.
IPH4102 high level of efficacy has been demonstrated in various pre-clinical models:
- Potent antitumor properties of IPH4102 were shown against human CTCL cells in vitro and in vivo in a mouse model of KIR3DL2+ tumors, in which IPH4102 reduced tumor growth and improved survival.
- The efficacy of IPH4102 was further evaluated in laboratory “ex vivo” assays using the patients’ own natural killer (NK) cells against their primary tumor samples in the presence of IPH4102. These studies were performed in patients with Sézary Syndrome; Sézary Syndrome is the leukemic form of CTCL and is known to have a very poor prognosis. In these experiments, IPH4102 selectively and efficiently induced killing of the patients’ CTCL cells. These results were published in Cancer Research in 2014.
Mechanism of action of anti-KIR3DL2
About IPH4102 Phase I trial
IPH4102 is currently in Phase I trial for the treatment of relapsed/refractory CTCL.
The Phase I trial is an open label and multicenter study. It is performed in Europe (France, Netherlands, United Kingdom) and in the US. Participating institutions include several hospitals with internationally recognized expertise: the Saint-Louis Hospital (Paris, France), the MD Anderson Cancer Center (Houston, Texas), the Stanford University Medical Center (Stanford, CA), the Ohio State University (Columbus, OH), the Leiden University Medical Center (Netherlands), and the Guy’s and St Thomas’ Hospital (United Kingdom). Approximately 60 patients with KIR3DL2-positive CTCL having received at least two prior lines of systemic therapy are expected to be enrolled in two sequential study parts:
- A dose-escalation part including approximately 40 CTCL patients in 10 dose cohorts. Its objective is to identify the Maximum Tolerated Dose and/or the Recommended Phase 2 Dose (RP2D);
- A cohort expansion part with 2 cohorts of 10 patients each in 2 CTCL subtypes (transformed mycosis fungoides and Sézary syndrome) receiving IPH4102 at the RP2D until progression. The CTCL subtypes may be adjusted based on the findings in the dose escalation part of the study.
The primary objective of this trial is to evaluate the safety and tolerability of IPH4102 in this patient population. The secondary objectives include assessment of the drug’s antitumor activity and identification of biomarkers of this activity. Clinical endpoints include overall objective response rate, response duration and progression-free survival.
Key Opinion Leader event chaired by Pr. Youn H. Kim, MD, Professor of Dermatology, Director of the Multidisciplinary Cutaneous Lymphoma Program and Medical Director of the Photopheresis Service at the Stanford Medical Center (New-York, October 2015)
Key Opinion Leader event chaired by Pr Martine Bagot, Head of the Dermatology Department at the Saint-Louis Hospital in Paris and co-discoverer of the target KIR3DL2 (Paris, December 2015) - in French
WARNING: some images may offend the sensibilities
- Battistella M et al, 2016. KIR3DL2 (CD158k) is a potential therapeutic target in primary cutaneous anaplastic large cell lymphoma. Br J Dermatol.
- Sicard et al., 2014. IPH4102, a Humanized KIR3DL2 Antibody with Potent Activity against CutaneousT-cell Lymphoma. Cancer Research
- Bouaziz et al., 2010. Absolute CD3+ CD158k+ lymphocyte count is reliable and more sensitive than cytomorphology to evaluate blood tumour burden in Sezary syndrome. Br J Dermatol.
- Bagot et al., 2001. CD4(+) cutaneous T-cell lymphoma cells express the p140-killer cell immunoglobulin-like receptor. Blood