There is growing appreciation of the depth of interaction between tumour cells and their microenvironment which modulates tumour growth, proliferation and immune suppression. The impact of these interactions on antibody immunotherapy is poorly defined. This presentation will discuss several key interactions between the host and the tumour in different anatomical niches that impact different types of antibody immunotherapy and how they might be targeted to improve treatment efficacy.

We report B cell class-switching to less immunoactive antibody isotypes and regulatory cytokine-expressing B cell subsets, promoted in alternatively-activated Th2-biased conditions in tumors. These form part of an anti-inflammatory environment associated with less favourable outcomes. Skewed B cell and immunoglobulin profiles reveal novel prognostic biomarkers, and point to opportunities for the development of antibody immunotherapies less prone to tumor-associated immunosuppressive forces.

ANV600 is a novel bispecific compound, which features an anti-IL-2 antibody/IL-2 fusion protein and a PD-1 binding moiety for targeted delivery of the IL-2R b/g-directed IL-2 to tumor antigen experienced PD-1+ T cells. The IL-2 is embedded in the antibody CDR-L1, thereby excluding the IL-2Ra from binding to the cytokine. The light chains of ANV600 naturally assemble with the corresponding heavy chain without the need of additional engineering. ANV600 has potent and selective proliferating effects on stem-like and effector CD8 T cells and markedly inhibits tumor growth in mouse tumor models.

Immunotherapies struggle in solid, so-called “cold” tumors due to the immunosuppressive tumor microenvironment (TME). M2-like tumor-associated macrophages (TAM) aid tumor growth and support the establishment of the TME. In contrast, M1 TAM shows promise in treating such tumors. We have successfully genetically modified macrophages with a chimeric cytokine receptor (ChCR), which induces a M1-like activation of the macrophages with tumoricidal properties when exposed to the M2-inducing cytokines IL-10 or TGFβ.

Siglecs are receptors expressed on immune cells that recognise sialic acid-containing glycans. Siglec-sialic acid axis regulates the immune responses and participates in tolerance to “self”-antigens in conditions like sepsis, autoimmune diseases, and cancer. Our research is focused on studying the interactions at the molecular level between Siglecs and their ligands to translate this knowledge into the development of novel therapeutics (either based in antibodies or modified glycans).

Recent reports have demonstrated that a population of tumor-specific T cells (Tstem-like) is critical for the response to anti-PD1 therapy. Interleukin-2 has been described to induce the differentiation of Tstem-like towards functional effectors. Unfortunately, IL-2 is toxic and detrimentally expands regulatory T cells. We developed PD1-IL2v, an immune cell-targeted IL-2v to promote an effective and long-term anti-tumor immune-response by expanding a novel CD8 T cell population, derived from Tstem-like.

Deka Biosciences has developed a platform to produce novel combination cytokine therapies aiming to mitigate known toxicity risks, while maintaining the anti-tumor function. Using targeting binding scaffolds facilitates fast uptake in the tumor microenvironment and reduces drug-antibody formation and systemic cytokine release syndrome. The unique configuration Deka’s Diakines create a new generation of far more stable cytokine therapy which can be given 3-times/week subcutaneously.

Immuno-STATs are Fc fusion molecules that can simultaneously engage, activate, and expand existing disease-specific T-cells to induce cancer cell destruction. Lead clinical candidate, CUE-101, targets HPV E7-specific T cells and demonstrates efficacy in late-stage head and neck cancer patients. With this clinical proof-of-concept and platform de-risking, we present our Immuno-STAT platform; its adaptability to target additional tumor types and modularity to expand potential of patient reach and diversity.

This presentation introduces innovative bispecific antibody immunocytokines targeting FcαRI, to enhance cancer therapy by recruiting myeloid effector cells to the tumor microenvironment, as a potential promising immunotherapeutic approach.

Tumor-infiltrating dendritic cells (DC) correlate with effective anti-cancer immunity and improved responsiveness to anti-PD-1 checkpoint immunotherapy. However, the upstream drivers of DC expansion and intratumoral accumulation are ill-defined. We find that interleukin-2-mediated, innate, and adaptive lymphoid cell-driven DC-poiesis in mice and humans resulted in pronounced expansion of type-1 and type-2 DCs with improved antigen presenting properties, which correlated with favorable anti-cancer responses.

Following ICB limitations, alternative therapeutic approaches use agonistic antibodies to target immune stimulatory receptors, such as GITR. Here, we elucidated the role of hFcgRs in the activity of GITR mAbs. By utilizing a mouse model that recapitulates human FcgRs expression, we identified novel FcgR-dependent mechanisms of GITR targeting that shift T cell ratios within the tumor. We developed novel IgG scaffolds of GITR mAbs that harness these mechanisms to increase the therapeutic efficacy.

cON-05 is a bispecific antibody comprising an arm binding to HSG (histamine-succinyl-glycine) and a Fab directed against oxMIF, the disease-specific conformational isoform of MIF (macrophage migration inhibitory factor). A two-step pretargeted radioimmunotherapy with cON-05 and a [177]Lu-labeled di-HSG peptide was tested in murine models of cancer. The treatment was well tolerated and led to significant tumor regression in colorectal cancer syngrafts and tumor growth inhibition in pancreatic cancer xenografts.

The inhibitory immune checkpoint FcgRIIB promotes resistance to antibody therapy acting on tumour and myeloid effector cells. We have developed function-blocking antibodies to FcgRIIB with differentiated mechanisms-of-action (BI-1206 and BI-1607). This talk will discuss how tailored FcgR blockade enhances anti-CD20, anti-Her2, anti-PD-1/L1, and anti-CTLA-4 therapeutic activity, and how it may help overcome antibody drug resistance and bring clinical benefit of immune checkpoint blockade to patients with poorly T cell-infiltrated tumours.

This presentation highlights the preclinical discovery of ARX622, a site-specific HER2-targeted TLR7 agonist ADC with stable conjugation, efficacy in large established tumor models, and a wide therapeutic index based on preclinical exposure data.