Aptevo Therapeutics’ Bispecific Antibody APVO436 Shows Robust T-Cell Activation With Minimal Cytokine Release
New Preclinical Data Presented at the 2018
Cytokine release syndrome (CRS) is a significant concern with T-cell activating therapies and has been associated with severe complications in clinical trials. Aptevo has previously published data on its first generation candidate, APVO414, showing reduced cytokine release upon T-cell engagement compared to another bispecific format (Mol Cancer Ther. 2016 Sep; 15(9); 2155-65).
New preclinical data presented at this year’s AACR Annual Meeting compare Aptevo’s second generation bispecific, APVO436, with an Aptevo-generated version of Macrogenics’ CD123 x CD3 dual-affinity re-targeting (DART) molecule, MGD006, evaluating T-cell activation, proliferation, cytotoxicity and cytokine secretion.
The data show that APVO436 and the Aptevo-generated version of MDG006 are both effective at stimulating a tumor-directed immune response by inducing comparable T-cell activation, proliferation and cytotoxicity. However, in these preclinical studies, APVO436 induced lower levels of several T-cell cytokines, including IFNγ, IL-2, IL-6, TNFα and several additional cytokines, suggesting a potential safety advantage with APVO436.
“We are especially excited about these latest data for APVO436, which continue to show robust T-cell engagement and cytotoxic activity with reduced levels of cytokine release. Importantly, IFNγ, IL-6, and TNFα are considered to be the most relevant cytokines responsible for dosing toxicities observed in clinical studies with T-cell engaging molecules, which suggests that APVO436 could offer the potential for reduced toxicities compared to other CD123 x CD3 T-cell engagers at comparable or higher doses,” said
“The accumulating data for APVO436 showing enhanced stability, extended half-life in rodents of up to 12.5 days, desirable manufacturing characteristics, and reduced cytokine release in preclinical studies, support our assessment of APVO436 as a “Best-in-Class” anti-CD123 x anti CD3 immunotherapeutic. We plan to file an IND for APVO436 in the upcoming weeks and commence a Phase 1 clinical trial of APVO436 later this year in acute myeloid leukemia and myelodysplastic syndrome,” noted Dr. Gross.
Acute myeloid leukemia (AML) is a form of blood and bone marrow cancer that is characterized by rapid disease progression. While treatments for AML are available, there remains a high unmet medical need for targeted therapies addressing patients with relapsed and refractory disease, and patients who cannot tolerate traditional chemotherapy.
Myelodysplastic syndromes (MDS) are conditions associated with abnormalities in the blood-forming cells in the bone marrow. Approximately 1 in 3 patients with MDS will progress to have AML.
In a poster session on
The data presented show that APVO436:
- Binds human CD123 and CD3-expressing cells with EC50 values in the low nM range and demonstrates potent target specific activity against CD123 expressing tumor cell lines at low effector to target ratios
- Potently induces endogenous T-cell activation and proliferation accompanied by depletion of CD123 expressing cells in experiments with primary AML subject samples and normal donor samples
- Demonstrates potent cytotoxic activity from antigen-expanded T cells from both normal and AML subject samples in the presence of CD123+ tumor cells upon re-exposure to APVO436
- Results in rapid and significant reduction in skeletal tumor burden indicating migration and engagement of T cells at the tumor site, in mice with established disseminated Molm-13 tumors and IV-implanted human T cells in therapeutic preclinical animal studies
- Induces lower levels of multiple cytokines compared to a different CD123 x CD3 format, when T cells were stimulated in the presence of CD123+ tumor cells
About APVO436 and the ADAPTIR Platform
APVO436 is an optimized, next generation bispecific antibody candidate designed to simultaneously target CD123 and CD3 and redirect T-cell cytotoxicity to the tumor. APVO436 was built on Aptevo’s proprietary ADAPTIR protein therapeutic platform. Focused on generating novel, targeted bispecific antibody-based immunotherapies for cancer and autoimmune diseases, the ADAPTIR platform offers key advantages over other bispecific formats, derived in part from the flexible and modular nature of the ADAPTIR structure. These advantages include: (i) achieving potent biological activity and extended half-life while retaining desirable manufacturing characteristics; (ii) unique properties for redirecting T-cell cytotoxicity (RTCC) compared to other bispecific platforms, including a favorable cytokine release profile; (iii) ability to achieve target-dependent induction of RTCC at lower concentrations than other bispecific antibody formats; and (iv) flexibility to build ADAPTIR candidates with diverse mechanisms of action, including RTCC, and targeted cytokine release and others. Two ADAPTIR molecules are currently in clinical development, with several more ADAPTIR bispecific immunotherapies in preclinical development.
Aptevo Product Portfolio
- IXINITY (coagulation factor IX [recombinant]) – is a third-generation recombinant human coagulation factor IX approved in
the United Statesfor the control and prevention of bleeding episodes and for perioperative management in adults and children 12 years of age or older with Hemophilia B.
ADAPTIR Clinical and Preclinical Pipeline:
- Otlertuzumab – a monospecific ADAPTIR candidate currently in Phase 2 clinical development for the treatment of peripheral T-cell lymphoma (PTCL). A previous Phase 2 clinical study evaluating otlertuzumab for the treatment of chronic lymphocytic leukemia (CLL) showed that otlertuzumab in combination with bendamustine, compared to bendamustine alone, demonstrated a significant increase in median progression free survival for the combination, from approximately 10 to 16 months.
- APVO414 – a bispecific ADAPTIR candidate, currently in Phase 1 development, targeting prostate specific membrane antigen (PSMA), an enzyme that is expressed on the surface of prostate cancer cells, and, CD3, a component of the T cell receptor complex expressed on all T cells. APVO414 redirects T cells to specifically kill PSMA expressing tumors and is being developed for metastatic castration-resistant prostate cancer, which is advanced prostate cancer that has spread to other organs and no longer responds to hormone blocking therapies.
- APVO436 – a bispecific ADAPTIR candidate currently in preclinical development targeting CD123, a cell surface receptor highly expressed on several hematological malignancies and CD3, a component of the T cell receptor. APVO436 engages T cells to initiate killing of tumor cells. Aptevo intends to file an IND and begin clinical development of APVO436 in 2018.
- ALG.APV-527 – a bispecific antibody candidate, partnered with
Alligator Bioscience, featuring a novel mechanism of action designed to simultaneously target 4-1BB (CD137) and 5T4, a tumor antigen widely overexpressed in a number of different types of cancer. 4-1BB, a costimulatory receptor on T cells, is known to enhance the immune response to cancer through activation of tumor-specific T cells and is believed to be a promising target for new immunotherapeutic approaches. ALG.APV-527 could potentially have utility in the treatment of a broad spectrum of cancers over-expressing the tumor antigen, including breast, cervical, non-small-cell-lung, prostate, renal, gastric, colorectal and bladder cancers.
- APVO210 – a bispecific ADAPTIR preclinical candidate with a novel mechanism of action based on targeted cytokine delivery. APVO210 is composed of a humanized anti-CD86 antibody fused with a modified form of IL-10 that specifically induces IL-10 signaling on antigen presenting cells, but not on lymphoid populations. APVO210 functions by suppressing immune responses and inducing certain tolerogenic responses and therefore may have potential benefit for the treatment of autoimmune and inflammatory diseases. Aptevo intends to file an IND for APVO210 in 2018.
- ROR1 Bispecific – a proof-of-concept bispecific candidate targeting ROR1, an antigen found on several solid tumors and hematologic, or blood-related malignancies. Initial preclinical data demonstrate redirected T cell killing of tumors expressing ROR1 in vitro and in vivo in animal models.
Safe Harbor Statement
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Any statements, other than statements of historical fact, including, without limitation, statements regarding potential milestone payments, Aptevo’s outlook, financial performance or financial condition, Aptevo’s technology and related pipeline, collaboration and partnership opportunities, commercial portfolio, milestones, and any other statements containing the words “believes,” “expects,” “anticipates,” “intends,” “plans,” “forecasts,” “estimates,” “will” and similar expressions are forward-looking statements. These forward-looking statements are based on Aptevo’s current intentions, beliefs and expectations regarding future events. Aptevo cannot guarantee that any forward-looking statement will be accurate. Investors should realize that if underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could differ materially from Aptevo’s expectations. Investors are, therefore, cautioned not to place undue reliance on any forward-looking statement. Any forward-looking statement speaks only as of the date of this press release, and, except as required by law, Aptevo does not undertake to update any forward-looking statement to reflect new information, events or circumstances.
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Senior Director, Investor Relations and Corporate Communications
Source: Aptevo Therapeutics Inc.