On September 4, 2025 Aptevo Therapeutics Inc. ("Aptevo" or the "Company") (NASDAQ:APVO), a clinical-stage biotechnology company focused on developing novel immuno-oncology therapeutics based on its proprietary ADAPTIRTMand ADAPTIR-FLEXTM platform technologies, reported expansion of its anti-cancer pipeline with the filing of two provisional patents for trispecific candidates, APVO452 and APVO451 for prostate cancer and multiple, additional solid tumor types with significant unmet needs (Press release, Aptevo Therapeutics, SEP 4, 2025, View Source [SID1234655771]). These programs build on the Company’s growing suite of CRIS-7-derived, CD3-directed molecules and are supported by compelling clinical validation from lead candidate, mipletamig, which has demonstrated strong clinical safety and efficacy for the treatment of acute myeloid leukemia (AML).

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A New Generation of CD3 Therapies

Aptevo’s CD3-engaging portfolio is anchored by mipletamig, a first-in-class CD123 x CD3 bispecific currently being evaluated in RAINIER, a Phase 1b/2 trial for frontline AML. In total, mipletamig has been evaluated in more than 100 patients across three trials, where mipletamig has consistently demonstrated high remission rates and a favorable safety and tolerability profile, with no observed cytokine release syndrome in frontline patients treated to date.

Building on this clinical validation, Aptevo previously expanded the suite with tumor-directed bispecifics APVO442 (prostate, PSMA x CD3) and APVO455 (solid tumors, Nectin-4 x CD3). All share the CRIS-7-derived CD3 binding domain, designed to deliver tumor-specific immune activation with a lower risk of systemic toxicity.

"It’s thrilling to introduce Aptevo’s first two trispecific immune cell engager biologics-and an exciting milestone for our team. Powered by our ADAPTIR-FLEX platform, these molecules are designed with a finely tuned mechanism of action that not only activates T cells in a tumor-specific manner but also modulates the immunosuppressive tumor microenvironment. This achievement reflects the monumental effort and exceptional talent of our highly capable team. Ultimately, we are creating therapeutics with the potential to fight cancer using multiple approaches of attack, but with a single molecule," said Peter Pavlik, PhD, Senior Director of Protein Engineering at Aptevo.

Trispecifics Designed to Modulate the Tumor Microenvironment

Expansion into trispecific molecule development represents a potentially profound emerging treatment option with the potential to unlock deeper, more durable anti-tumor responses by simultaneously engaging multiple immune pathways while limiting systemic toxicity. Solid tumors remain difficult to treat because the tumor microenvironment (TME) actively suppresses immune responses, limiting the efficacy of current therapies. To address this, Aptevo is advancing a new class of trispecific engagers that unite tumor targeting, T cell activation, and immune costimulation in a single molecule. This design has the potential to be delivered safely while harnessing the body’s own immune system to fight tumors locally in the tumor microenvironment.

APVO452 targeting PSMA, CD3, and CD40, is designed to address prostate cancers via PSMA targeting. This molecule works like a three-in-one tool: One-part locks onto the tumor, another part activates the body’s T cells to fight, and the third part reprograms other immune cells that normally protect the tumor. In preclinical studies, this trispecific approach was able to effectively kill tumor cells and, importantly, only switched on the immune system when tumor cells were present

APVO451 similarly incorporates trispecific design principles, targeting Nectin-4, CD3, and CD40, and is intended for a broad range of solid tumors. Early data indicate potent, anti-cancer activity that attacks cancer in multiple ways, increasing the opportunity to address critical unmet needs by offering treatment options for multiple solid tumors

"Beyond ramping up immune cell activity, there is a need for cancer treatments that achieve the true goal of immunotherapy in oncology: to restore balance to the immune system so it can kill tumor cells, while avoiding dangerous side effects. Tumor cells don’t exist in isolation. There is a complex tumor environment that includes other types of cells and structures-that signal to each other, increasing tumor growth and progression, and suppressing the body from fighting back. It’s not one single barrier; it’s a whole network of barriers working together," said Lynn Bonham, PhD, Senior Director of Translational Pharmacology at Aptevo. Bonham continued, "Our new trispecific molecules, APVO452 and APVO451, are built to tackle tumors on several fronts at once. They lock onto the tumor itself, activate T cells to attack it, and reprogram suppressive immune cells so they help the fight instead of holding it back."

Looking Ahead

With the addition of APVO452 and APVO451, Aptevo now has eight bispecific and trispecific therapeutic candidates, including five molecules that employ the CRIS-7-derived CD3 pathway. This dual strategy positions the Company at the forefront of next-generation T cell engagers, with a pipeline purposefully designed to address both hematologic and solid tumor cancers such as AML, lung and breast cancers and multiple other solid tumor types.