A Novel Multimeric IL15/ IL15Rα-Fc Complex to Enhance Cancer Immunotherapy

SUMMARY OF INVENTION

T-cells and NK cells can cure human cancers. Their success requires continued persistence in vivo and efficient trafficking to tumor sites. To date, cytokine IL-2 remains the only clinically approved cytokine therapy available to achieve that, but toxicities can be severe. Cytokine IL-15 offers similar capabilities, but without the unwanted side effects seen with IL-2, such as capillary leak, activation-induced T-cell death, and induction of Tregs.

MSK researchers have developed a novel multimeric IL15/IL15Rα-Fc complex, which shows substantial enhancement of anti-tumor effect in animal models, compared to alternative strategies. Presentation as an IL15-IL15Rα complex magnifies the cytokine function and addition of the Fc protein prolongs the cytokine half-life. MSK’s novel multimeric IL15/IL15Rα-Fc complex is expected to enhance existing immunotherapies, including those using antibodies and antibody constructs and BCG (Bacillus of Calmette and Guerin).

Significantly, MSK’s novel technology outperforms a directly competing technology:ALT-803, an IL-15 mutant plus dimeric IL-15RαSushi-Fc fusion protein complex, that has been proven safe and effective in preclinical and clinical studies. Our research demonstrates that ALT-803 is substantially less effective when compared to MSK’s IL-15 complex, especially when administered by the subcutaneous route.

ADVANTAGES

IL15/IL15Rα complex has proven significantly more potent in vivo than ALT-803: in xenograft models, it demonstrated longer serum half-life, and enhanced anti-neuroblastoma and anti-melanoma cytotoxicity in the presence of NK cells + IgG antibodies, or T cells + BsAb.
GMP product already has been manufactured
A GLP toxicology study in mice and a non-GLP toxicology study in non-human primates recently confirmed the lack of toxicities of these constructs at clinically relevant dosages

MARKET OPPORTUNITY

The complex can be used in combination not only with NK cell-engaging antibodies or T-cell-engaging bispecific antibodies in cancer immunotherapy, but also with chimeric antigen receptor (CAR) T-cell therapy and immune checkpoint inhibitors, which indicates that market size will be substantial.
Recombinant human IL-15 or IL15/IL15Rα complex have been used in clinical studies either alone or in combination with other antitumor therapies to treat a range of both hematological and solid tumors, such as melanoma, renal cell cancer, pancreatic cancer, lung cancer, bladder cancer, and indolent B cell non-Hodgkin lymphoma (used alone or in combination with antibodies or with T-cells). Besides cancer, IL-15 has a major role in infectious diseases, including viral, fungal, and bacterial infections, as well as immunodeficiencies. IL-15’s efficacy in preclinical HIV models is well known and its potential for viral infections and pandemics (e.g. Covid-19) is large.
Another area of medical need with potential would be using the MSK IL-15 complex together with BCG to treat non-muscle invasive bladder cancer that is unresponsive to BCG treatment alone.

LEAD INVESTIGATOR

Nai-Kong Cheung, MD, PhD. Laboratory Head, Memorial Hospital Research Laboratories; Enid A. Haupt Chair in Pediatric Oncology

PATENT INFORMATION

PCT Application PCT/US2020/013232 filed on Jan 10, 2020. US National 17/421,846 filed on Jul 9, 2021.
National applications filed in Canada, Europe and Australia

PUBLICATION