Tumor cells avoid immune recognition through inactivating STING. Selective activation of the STING pathway may be achieved through inhibition of TREX1, a DNA exonuclease that modulates cGAS/STING signaling that is induced in tumor cells following genetic instability or therapeutic intervention. We identified TREX1 inhibitors with picomolar potency and drug-like physicochemical properties. Lead molecules with activity in cell-based assays had anti-tumor activity in combination with doxorubicin and were cytotoxic in DNA repair-deficient tumor cells. This new class of STING therapeutics can activate the cGAS/STING pathway to initiate tumor immunity and inhibit DNA repair orthogonal to existing DNA repair mutations.

Evaluation of Fc effector mechanisms of therapeutic antibodies is an important regulatory requirement. Eurofins DiscoverX’s MOA-reflective KILR cytotoxicity assays enable precise quantitation of multiple effector-mediated MOA’s including ADCP & ADCC applications. These dye-free, radioactivity-free assays measure direct target cell killing. Here we share phase-appropriate data for several KILR bioassay models demonstrating these assays are fit-for-purpose for screening, characterization, & relative potency applications in lot-release testing.

We designed and generated six large (>1011 each) human VH and VL antibody domain libraries displayed on phage (Chen W et al PNAS 2009; Chen C et al Star Protocols 2021; Sun Z et al Frontiers in Immunology 2022) from which we selected a number of binders against cancer-related targets. The binders were highly effective against cancer models as CAR Ts (Schneider D et al, Frontiers in Oncology, 2018; Sun Z et al bioRxiv, 2022) and ADCs (Sun Z et al bioRxiv, 2022), and exhibited good developability. Some of the binders could be evaluated in human clinical trials.

The optimal immunotherapeutic strategy for pediatric solid tumors is unknown and new targets are needed. We identified glypican 2 (GPC2) as a MYCN-activated, differentially-expressed, cell surface oncoprotein in neuroblastoma and other cancers. To therapeutically leverage GPC2, we developed the fully human D3-GPC2-IgG1 and conjugated it to pyrrolobenzodiazepine (PBD) dimers to generate an antibody drug conjugate that safely induces specific and durable cytotoxicity in neuroblastoma and other cancer preclinical models.

Antibody-drug conjugates (ADCs) are an emerging class of therapeutics that combine target-specific capabilities of monoclonal antibodies (mAbs) with cytotoxicity chemotherapy. Technologic advancement incorporating humanized mAbs, customizable linkers, and payloads with cytotoxicity in the picomolar range have led to a rebirth of ADCs as an efficacious class of anti-cancer therapeutics. In this talk, we will provide an overview of ADCs that show promise in non-small cell lung cancer.

• Target validation
• Preclinical models
• Dissecting mechanism
• Designing appropriate clinical trials, relevant endpoints ​
• Managing expectations; fish or cut bait
  

Individualized neoantigen-specific immunotherapy (iNeST) requires robustly expressed clonal neoantigens for efficacy, but tumor mutational heterogeneity, loss of neoantigen expression, and variable tissue sampling present challenges. We show that tumor type, multi-lesion sampling, neoantigen expression, and HLA allele retention are important factors for iNeST targeting and patient selection, and may also be important factors to consider in the development of biomarker strategies.

Checkpoint blockade immunotherapies have transformed the standard of care and outcomes for many cancers, but more than 60% of patients still do not experience a durable clinical response from these treatments. We used single cell and machine learning analysis to show that T-cell receptors are not the sole determining factor in Tconv vs. tTreg cell fate decisions, with conclusions offering new biomarker and novel combinatorial treatment options for checkpoint blockade immunotherapies.

In the highly competitive immune-oncology (I-O) space, effective identification and differentiation of potential therapeutics requires a detailed understanding of mechanism of action (MOA). To maximize the value of sophisticated antibody discovery technologies, MOA needs to be understood at the earliest stages of drug discovery. In these initial stages, candidate numbers can measure in the thousands and precious sample quantities are stretched thin across numerous discovery platforms. This talk will focus on a strategy of I-O therapeutic selection supported by high-throughput surface plasmon resonance (HT-SPR) to increase the potential for efficacious and commercially differentiated antibodies. By front loading characterization efforts in the discovery phase, this approach enables an evolving selection of therapeutic leads dependent on program objectives, biological discoveries, and commercial pressure.

The ability to engineer primary human B cells to differentiate into long-lived plasma cells and secrete de novo proteins permits the creation of novel plasma cell therapies for the next generation of immunotherapies. Efficient engineering is achieved by gene editing in combination with AAV DNA templates and results in site-specific gene insertion. Our results demonstrate a novel strategy for modifying human plasma cells to secrete therapeutic proteins.

Tallac Therapeutics focuses on novel therapeutics engaging both innate and adaptive anti-tumor immunity. TAC-001 is an antibody-oligonucleotide conjugate designed for targeted TLR9 activation in B cells. Systemic TAC-001 administration leads to robust single agent activity in checkpoint inhibitor resistant and refractory murine tumor models, accompanied by increased B cell infiltration, T cell effector functions and modulation in myeloid cells within the tumor microenvironment. TAC-001 is in development for solid tumors.

While the field of autoimmunity typically explores the “pathologic” effects of the immune system once tolerance is broken, there is no rationale to preclude autoimmunity from having a potentially beneficial phenotype. Since antibodies can initiate tumor rejection and drive anti-tumor immunity, we seek to discover novel targets and autoantibodies that are functional and help control cancer progression.

Compared to CAR T cells, CAR-NK cells offer some significant advantages, including i) better safety, such as minimal cytokine release syndrome, neurotoxicity and graft-versus-host disease, ii) multiple mechanisms for activating cytotoxic activity, and iii) high feasibility for “off-the-shelf” manufacturing. We are developing the next generation of CAR-NK cells by combining tumor-specific CAR, additional armors, and cytokine-induced memory-like NK cells, with a goal to achieve effective and durable anti-tumor response in patients.

T cell-based immunotherapy is a promising treatment for many cancers but has low rates of response and durability, challenges that may be overcome by increasing the number of tumor antigen-specific T cells. Using humanized Fc?R mice, we demonstrate that engaging human FcγRIIIB, which is selectively expressed on abundant blood neutrophils with an anti-FcγRIIIB-antigen conjugate reprograms them into potent antigen-presenting cells (nAPCs). We provide evidence that: 1) nAPCs promote robust antigen-specific and antigen-agonistic T cell activation that is equivalent to or exceeds monocyte-derived dendritic cells, 2) nAPC-derived IL-15 plays an important role in T cell activation. 3) nAPCs promote anti-tumor immunity.

Antibodies and other macromolecules play critical roles in modern cancer treatments, but delivery challenges limit applications to extracellular and membrane-bound targets. Here, we describe the selective disruption of the STAT3 signaling pathway via lipid nanoparticle-mediated antibody delivery. Our findings highlight emerging opportunities for using macromolecules to selectively interfere with intracellular signaling pathways dysregulated in cancer cells and other cells that arise in the tumor microenvironment.

Parthenon Therapeutics discovers and develops first-in-class therapeutics with differentiated single agent activity to reprogram the Tumor Microenvironment and improve cancer treatment. Our product candidates are applicable across broad tumor types (lead project PRTH-101, FIH 2023), including the significant number of Immune excluded tumors with unfavorable clinical outcome and inadequate response to therapy. Our pipeline being orthogonal to CPIs opens a new front to improve the therapeutic index with CPI combinations.