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New Autoimmune Candidate APVO210 Demonstrates Targeted Cytokine Delivery for Application in Various Autoimmune and Inflammatory Diseases
In a presentation entitled, “APVO210 an ADAPTIR Targeted Cytokine Delivery Molecule for Autoimmune and Inflammatory Diseases,” Dr.
Cytokines function by promoting or suppressing a variety of cellular functions, including inflammatory responses. Unregulated inflammation can result in disease and chronic inflammatory conditions like IBD. IL-10 is a cytokine that is known to suppress inflammation. However, IL-10 also has stimulatory functions on lymphocytes, enhancing B cell proliferation and cytotoxic T cell function, reducing its potential anti-inflammatory therapeutic properties.
APVO210 is a novel targeted cytokine therapeutic based on Aptevo’s ADAPTIR modular protein therapeutic platform. It targets a modified version of IL-10 to CD86+ cells, increasing its immunosuppressive properties without stimulating T and B lymphocytes, as demonstrated in preclinical studies. APVO210 improves the anti-inflammatory properties of IL-10 in two ways. First by specifically targeting cells expressing CD86, such as monocyte, macrophage, and dendritic cells, and secondly by delivering a modified form of IL-10 that does not stimulate lymphocytes. This lack of lymphocyte stimulation may reduce the toxicities previously observed following repeat administration of IL-10 in humans, and potentially allow for increased dosing. In addition, APVO210 has demonstrated a longer half-life in non-human primates and may improve dosing regimens.
Preclinical data confirm the mechanism of action of APVO210 and show the effective targeting of APVO210 to antigen presenting cells with limited effects on lymphocytes. Pharmacokinetic studies also demonstrate that APVO210 is potent and well tolerated in preclinical models at doses up to 10 mg/kg in single dose studies in non-human primates, and 30-fold more potent than CTLA4-Ig in in vitro and in vivo animal systems.
Additionally, preclinical data show proof of concept for APVO210 in a humanized transplant model. In a prophylactic model of graft versus host disease (GvHD), APVO210 showed strong inhibition of T cell expansion at very low doses (~70 ug/kg) and reduced the accumulation of cytokines in circulation. In this model, APVO210 was 100-fold more potent than abatacept at maximum inhibition of T cell expansion.
“Targeted cytokine delivery represents an evolving approach for the treatment of autoimmune and inflammatory diseases and we are excited to expand the application of our ADAPTIR technology platform to include additional candidates like APVO210, featuring a novel mechanism of action distinct from redirected T cell cytotoxicity (RTCC), which is the basis of many of our ADAPTIR oncology candidates,” remarked Dr.
ADAPTIR Bispecific Antibody Platform: Differentiating Characteristics
- Unique Homodimer Structure - simplifies candidate generation; facilitates rapid substitution of target binding domains to evaluate numerous candidates simultaneously
- Bivalent for Both Binding Domains - increases the avidity and potency of ADAPTIR candidates
- Unique IgG Fc ‘Backbone’ - extends the half-life of ADAPTIR molecules (up to ~12.5 days in rodents)
- Antibody-like Production Processes – demonstrated capability to produce up to 2.0g/L comparable to traditional antibody manufacturing processes
- Improved Yield and Cost of Goods - use of a single gene and ease of CHO cell line production enhances ADAPTIR bispecific manufacturing productivity
- Flexible Platform Technology – ability to produce protein therapeutics with different structural elements fused to an antibody backbone for different mechanisms of action.
ADAPTIR Clinical and Preclinical Portfolio:
- 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.
- Otlertuzumab – a monospecific ADAPTIR candidate currently in Phase 2 development for the treatment of chronic lymphocytic leukemia (CLL). Data from a Phase 2 clinical trial evaluating 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.
- 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 kill tumor cells.
- 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 an undisclosed tumor antigen. 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, in multiple solid tumors 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.
- 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.
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