Bristol Myers Squibb (BMS) and Nektar Therapeutics announced a collaboration in which BMS’ PD-1 checkpoint inhibitor (Opdivo, nivolumab) will be combined with Nektar;s CD-122 agonist NKTR-214.
Opdivo, a monoclonal antibody, works by binding to PD-1 expressed on T-cells, thereby inhibiting its interaction with PD-L1, which is expressed on cancer cells. Blocking this interaction protects cytotoxic T-cells from dying, allowing them to attack the cancer (Figure 1).
What is CD-122?
CD-122 is the beta subunit of the interleukin-2 (IL-2) receptor:
The interleukin 2 receptor, which is involved in T cell-mediated immune responses, is present in 3 forms with respect to ability to bind interleukin 2. The low affinity form is a monomer of the alpha subunit and is not involved in signal transduction. The intermediate affinity form consists of an alpha/beta subunit heterodimer, while the high affinity form consists of an alpha/beta/gamma subunit heterotrimer. Both the intermediate and high affinity forms of the receptor are involved in receptor-mediated endocytosis and transduction of mitogenic signals from interleukin 2. The protein encoded by CD-122 represents the beta subunit and is a type I membrane protein.What is IL-2 and why is it important?
IL-2 is a critically important cytokine in the homeostasis and activation of the immune system. It is a major cytokine involved in precipitating adaptive immune responses, stimulating T-helper (CD-4) and cytotoxic (CD-8+) – see Figure 3. However, IL-2 also maintains homeostasis by stimulating Treg cells, which suppress adaptive immune responses.
IL-2 is approved for the treatment of patients with renal cancer (RCC) and melanoma; both tumors are immunologically modulated cancers, demonstrated by spontaneous regression of patients with advanced disease who were not receiving any systemic treatment. High does therapy with IL-2 is very beneficial to patients with RCC and melanoma (Figure 4).
What is NKTR-214?
NKTR-214 is an agonist of CD-122 that stimulates cytotoxic T-cells (CD-8+) and NK (natural killer cells). It is IL-2 conjugated with polyethylene glycol (PEG) to mask the region of IL-2 that interacts with the IL2Rα subunit responsible for activating immunosuppressive Tregs (regulatory T-cells), biasing activity towards tumor killing CD8+ T cells. NKTR-214 is a biologic prodrug consisting of IL2 bound by 6 releasable polyethylene glycol (PEG) chains (Figure 5).
In preclinical studies, NKTR-214 demonstrated a mean ratio of 450:1 within the tumor micro-environment of CD8-positive effector T cells, which promote tumor destruction, compared with CD4-positive regulatory T cells, which are a type of cell that can suppress tumor-killing T cells.2 Furthermore, a single dose of NKTR-214 resulted in a 500-fold AUC exposure within the tumor compared with an equivalent dose of the existing IL-2 therapy, enabling, an antibody-like dosing regimen for a cytokine. In dosing studies in non-human primates, there was no evidence of severe side effects such as low blood pressure or vascular leak syndrome with NKTR-214 at predicted clinical therapeutic doses.
Clinical trials of NKTR-214
A Phase 1/2 Dose Escalation and Expansion Study Of NKTR-214 In Subjects With Locally Advanced Or Metastatic Solid Tumors (NKTR-214) is currently recruiting patients.
This is a first in human, open-label, sequential dose escalation and expansion Phase 1/2 study of NKTR- 214 in adult patients with locally advanced and metastatic solid tumors. The Phase 1 stage of the study is designed as an open-label dose escalation trial of NKTR-214 in participants with locally advanced or metastatic solid tumors. The goal of the dose escalation stage of the study is to find the recommended phase 2 dose, to evaluate the efficacy of NKTR-214 by assessing the objective response rate and to evaluate the safety of NKTR-214. Immunological biomarkers in plasma and tumor samples will also be measured. Following this Phase 1 stage of the study, the Phase 2 expansion stage of the study will evaluate NKTR-214 in specific tumor settings.
In addition to this, Nektar Therapeutics has entered into a Phase 1/2 clinical research collaboration with The University of Texas MD Anderson Cancer Center to evaluate NKTR-214 in a variety of tumor types as a monotherapy and in combination with checkpoint inhibitors such as anti-PD-1 (Opdivo, nivolumab) and anti-CTLA-4 (Yervoy, iplilimumab).
Rationale for combining nivolumab and NKTR-214
There is sound rationale for combining NKTR-214 and checkpoint inhibitors – the former has the potential of accelerating the CD8+ specific immune response against the tumor (without stimulating Treg cells, which suppress CD8+ cells) and the latter can prevent abrogation of the immune response, enabling stronger immune attack for a longer period. That, of course, is the hope.