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Advancing apace with ADAPTIR
SEATTLE—As 2019 heads further into its second quarter, it’s already been a productive year for biotechnology company Aptevo Therapeutics Inc., which presented positive preclinical data at the recent AACR 2019 Annual Meeting.
The data in question was for two of the company’s ADAPTIR bispecific candidates: APVO436, a bispecific antibody candidate that targets CD123 and CD3; and ALG.APV-527, a bispecific antibody candidate that targets 4-1BB and 5T4.
Data for APVO436 showed that the compound can induce the generation of functional memory T cells with cytolytic function from naive T cells, has an extended serum half-life of 4.5 days in a non-clinical species, and has good tolerability, antibody-like clearance and volume of distribution parameters. In addition, APVO436 had potent T cell cytotoxicity with a reduced cytokine release, something that could give it an edge over similar compounds. Cytokine release can be an issue in cancer treatment.
“Cytokine release, if it’s extreme, can lead to what’s referred to as a cytokine storm in a person, and it can ultimately, at least in some trials that have been run, lead to death of a patient. So it can be a serious outcome as a result of the drug being introduced to a person’s body,” Jeff Lamothe, head of business development at Aptevo, tells DDNews.
Compared to a mock version of a competitor anti-CD123 and anti-CD3 bispecific molecule that Aptevo created, APVO436 showed reduced levels of cytokine activation, while still leading to the activation and proliferation of naive CD4 and CD8 T cells in the face of CD123-positive tumor target cells.
“The reduction in cytokine release we’ve observed in preclinical studies with APVO436, vis-à-vis a competitor molecule, is a particularly interesting finding,” noted Dr. Jane Gross, chief scientific officer for Aptevo. “The possibility that APVO436 could stimulate an effective immune response against CD123-positive tumors, but with a more controlled cytokine release profile, is especially intriguing, offering the potential for reduced toxicities compared to other CD123 x CD3 T-cell engagers at comparable or higher doses. We also show new data demonstrating the differentiation of a memory T cell population by APVO436 in preclinical studies which can potentially contribute to a more sustained clinical response. We are excited to have commenced our Phase 1/1b clinical trial of APVO436 in patients with AML and MDS and are hopeful that the emerging clinical data will validate our preclinical safety hypothesis. We look forward to reporting a preliminary ADA read-out for APVO436 in the third quarter of 2019 and reporting preliminary Phase 1 safety data in the fourth quarter of 2019.”
As for ALG.APV-527— a novel tumor-directed anti-4-1BB x anti-5T4 bispecific antibody candidate being co-developed with Alligator Bioscience against a variety of 5T4-positive solid tumors—the data presented at AACR showed the antibody candidate could promote potent, selective immune activation in the presence of 5T4 antigen-expressing tumor cells. Toxicology studies have suggested a favorable safety profile as well, with no major changes in liver enzyme levels, cytokine levels or immune cell populations. The candidate also showed an extended serum half-life of five to seven days when administered intravenously.
In addition to these compounds, Lamothe tells DDNews that the company is also advancing APVO210, an autoimmune ADAPTIR candidate that targets a modified IL-10 and that he says “has broad applicability across multiple indications.” The antibody entered the clinic in March—Aptevo’s second candidate to make it to the clinic—and is being evaluated in healthy patients.
“We have data coming out this year in Q3 and Q4, both on APVO436 and APVO210, and we anticipate starting clinical trials on ALG.APV-527 early in 2020,” he adds.
“There are many points of differentiation for the ADAPTIR platform and its candidates from other competitor products and structures that are out there,” Lamothe remarks. “I think the most important point we try to stress with people is that our structure is a homodymer, where I think all of our competitors are manufacturing heterodymers. And one of the principal advantages of a homodymeric structure is that it is more efficient to manufacture. So beyond the drug development point, when you think about getting the candidate into the clinic—and ultimately out of the clinic and into patients on a commercial basis—that’s where efficient manufacturing structure is beneficial from a cost perspective, as well as from a production consistency and certainty perspective.”