Upregulating to success

Specially designed fusion protein ALKS 4230 could target many solid tumors

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DUBLIN—The labs at Alkermes have pinpointed a novel protein that improves overall tolerability and efficacy when targeting many solid cancerous tumors. ALKS 4230 is a specifically designed fusion protein that serves to upregulate the immune system by targeting tumor-killing CD8 T cells and natural killer (NK) cells while bypassing the high-affinity interleukin-2 (IL-2) receptors which have proven problematic in certain tumors. Often, with IL-2, there is a race to reach efficacious dosing before requiring stabilizing interventions to offset associated toxicities.
“We used the technology of circular permutation to fuse different pieces of molecules to see if we could get different binding—that is where ALKS 4230 came from,” says Blair Jackson, senior vice president of corporate planning. “It is really interesting the translation between biological capability and understanding the biology of the cell that allows us to identify opportunities.”
The opportunities they have discovered with ALKS 4230 indicate a novel cytokine with potential antitumor efficacy while avoiding the tolerability issues associated with IL-2, which include significant adverse effects.  Specifically, ALKS 4230 was 1,000 times less potent than an IL-2 in activating regulatory T cells which can suppress cancer-fighting immune response.
This approach offers a broad range of potential tumor targets, but does present the corollary challenge of finding ideal patient candidates to test on. What it does allow, though, is the ability to partner with other treatments, combining with PD-1 inhibitors to be more stable in the body, behaving differently to reduce toxicity and intolerability.
"Targeting the IL-2 pathway has shown significant efficacy in renal cell carcinoma and melanoma, however, the broader and more prevalent use of this approach in treating cancer has been limited by the toxicity profile and side effects associated with currently available IL-2-based therapy," said Dr. Marc Ernstoff of the Roswell Park Comprehensive Cancer Center, and publication co-author. "These preclinical data demonstrated that ALKS 4230 selectively activated and expanded cancer-fighting cells in mice with less toxicity than conventional high-dose IL-2 therapy. These data support further clinical evaluation of ALKS 4230 as a potential novel cytokine-based cancer immunotherapy."
ALKS 4230 upregulates the immune system by binding to the intermediate affinity receptor, rather than the previously targeted high affinity receptor. Intermediate receptors are those most expressed in CD8 T cells and NK cells, increasing the therapeutic window and the efficacy. By blocking the receptor they did not want to bind on to the IL-2, they opened the pathway to bind to the intermediate receptor, enhancing tumor-killing cells. 
Mouse models exhibiting a lung metastasis showed a 100-percent inhibition in tumor growth with ALKS 4230 when compared against the efficacy of IL-2 which shows a 70-percent inhibition. Other notable findings in the release of preclinical data note that they saw an expansion of CD8 T cells and NK cells. These benefits emerged whether administered intravenously or subcutaneously.
Until recently, Alkermes was best known for its work with central nervous system (CNS) disorders. They took advantage of the breadth of experience in their Boston-based team and looked to use their platforms to tackle oncology while maintaining their CNS focus. The success of ALKS 4230 reinforces their strong entry to the oncology space. Jackson sees many potential advances in the utilization of ALKS 4230 by combining it with various checkpoint inhibitors and tyrosine kinase inhibitors.
“PD1s are just the beginning of the story,” explains Jackson. “Looking at other molecules, we can enhance the body’s removal of tumors. Any therapy where you enhance DNA damage repair (PARPs), it brings antigens to the surface of the tumor, which allows for that tumor to be removed. There’s a lot of different lanes we can take where we think this could be really efficacious.”
ALKS 4230 research is moving into Phase 2 clinical trials as part of the company’s ARTISTRY clinical development program. The program includes both intravenous and subcutaneous dosing studies, where ALKS 4230 is being administered as a monotherapy and in combination with pembrolizumab. The dose escalation phase of the intravenous study has been completed and recommended phase two dose has been selected. The subcutaneous study continues in the dose escalation phase. Alkermes plans to reveal new data from these trials later this year.
Concludes Jackson: “We are seeing T cells do what we want with a beautiful tolerance. Now we need to see efficacy and disease stabilization so we can augment PD1 therapy across different tumor lines.”

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