Immunostimulatory antibodies (ISAs) represent a promising strategy for cancer immunotherapy by enhancing immune responses. However, to develop more effective therapeutics, we need a deeper understanding of the structure-function relationship under-pinning their activity. To investigate whether hinge restriction can provide augmented agonism, we explored a series of mutations in the IgG hinge in different ISAs and employed a host of biophysical, biochemical, and cellular assays to ascertain binding properties and activity. These orthogonal and complementary approaches provide a rational means to develop more powerful ISAs to deliver more effective anti-cancer treatments.

Neutrophils (PMN) have often been described to promote tumour growth and invasiveness. However, when PMN are properly activated they can also effectively kill tumour cells. During this presentation approaches will be presented which may recruit PMN’s tumour-cell killing activity to increase the efficacy of tumour immunotherapy.

The Il-6/AUF1 positive feedback loop plays a major role in the activation of breast cancer-associated fibroblasts. We have shown that tocilizumab, an IL-6R inhibitor, can target this loop and inhibits the cancer-promoting cross-talk between cancer cells and their supporting stromal fibroblasts.

To date basophils have received little attention in cancer. We found basophil markers in the tumour microenvironment and circulating basophils in cancer patient blood. Patient survival outcomes were associated with the presence of these cells. We demonstrated that circulating basophils from patient blood can be activated by immune stimuli ex vivo and used the basophil-activation test (BAT) to study the potential for Type I hypersensitivity reactions to anti-cancer IgE therapeutics.

Most cancer patients fail to respond to immune checkpoint blockade immunotherapies (ICB), and ICB-induced IFN-gamma (IFNg) drives immunotherapeutic resistance by altering the tumour-intrinsic immune phenome associated with the upregulation of immune checkpoints and immunosuppressive mediators. A major bottleneck to improving the efficacy of IFNg-inducing immunotherapies is our lack of knowledge as it pertains to the oncogenic pathways that drive tumour-intrinsic differences in IFNg sensitivity.

Small cell lung cancer (SCLC) is the most aggressive form of lung cancer and patients lack durable responses to immune checkpoint blockade. This is likely due to epigenetic MHC-I silencing and the paucity of infiltrating effector CD8 T cells. Through multi-modal analysis of SCLC patient biopsies, we uncovered significant γδ T cells infiltration in the tumour microenvironment compared to CD8 or NK cells. γδ T cells have the potential to recognise surface ligands on SCLC cells and initiate cytotoxic killing independent of the MHC-I/peptide axis. Therefore, bispecific antibodies may be used to encourage γδ T cell recognition of SCLC cells.

Alligator´s Neo-X-Prime platform is built to induce efficient neoantigen cross-priming of tumour-specific T cells to drive efficacy of CD40 targeting therapies and to modulate the tumour microenvironment. The platform is built on bispecific antibodies targeting CD40 and highly expressed tumour-associated antigens (TAA). The lead candidate, ATOR-4066, targets CD40 and CEACAM5 and induces superior anti-tumour activity by myeloid cell-mediated and T cell-dependent mechanisms.

Vγ9Vδ2-T cells represent a relatively homogeneous population of proinflammatory immune effector cells. The presentation will provide an update on the preclinical and early clinical development of bispecific Vγ9Vδ2-T cell engagers as a novel approach for cancer immunotherapy.

Our genetic-engineered plasmacytoid dendritic cells (UpDC) are a novel cell therapy that may change the paradigm of solid-tumour treatment by the inhibitory effects on tumour cells of Type I interferons, combined with the release of pro-inflammatory cytokines, resulting in recruitment and engagement of other immune cells. This activity is further complemented by direct tumour- cell killing. We are currently moving towards a Phase I study of autologous UpDCs.

Engineering antibody-cytokine fusion proteins (immunocytokines) for cancer therapy. Immunocytokines can increase the therapeutic index of the cytokine payload. Immunocytokines can selectively localise at the tumour site. Immunocytokines can induce potent anti-cancer activity either alone or in combination with other immunomodulatory drugs.

I will present our latest work on our novel anti-cancer immunotherapy using a retargeted adenoviral vector. Targeting overexpressed tumour cell receptors with binding proteins, we achieve localised IgA-antibody and CD47-blocker production. Mechanistic studies of activity will be demonstrated in biological models with increasing levels of complexity, e.g., focusing on neutrophils utilising antibody-dependent cellular cytotoxicity and macrophages employing antibody-dependent cellular phagocytosis for efficient tumour cell elimination.

Our group pioneered the design of activatable chemokine conjugates for targeting of tumour-associated macrophages, compatible with both fluorescent and therapeutic cargos. These constructs exploit the high expression of chemokine receptors and the activity of cysteine cathepsins to target tumour-associated macrophages over other macrophages and immune cells in tumours. Furthermore, our group has also designed novel fluorogenic reagents to detect physiological concentrations of active gransymes as biomarkers of immune-mediated anticancer activity.

LSTA1 (certepetide), is a novel investigational drug that selectively actuates the CendR active transport mechanism, which ferries anti-cancer drugs more efficiently through stroma and into solid tumours. LSTA1 has been shown to modify the tumour microenvironment by depleting intratumoural immunosuppressive cells thereby combating anti-cancer agent resistance. LSTA1 has also been shown to inhibit metastases in highly fibrotic tumours. Validating preclinical and positive clinical data in pancreatic ductal adenocarcinoma and other solid tumour cancers will be presented.

InCephalo’s compartment lock (C-Lock) technology allows high local CNS levels at minimal systemic exposure, increasing the therapeutic index for locally applied biologics such as antibodies or antibody-Fc-fragment fusions to treat neurological diseases. InC01 is a C-Locked IL-12-based biologic which InCephalo develops for the treatment of brain cancer. Preclinical data on the development and proof of concept in relevant murine and human ex vivo models will be presented.

To achieve spatial control of cytokine bioactivity upon drug administration, we have evolved a proprietary biologics platform integrating a strategic plug-and-play assembly of modular, biomolecular building blocks into therapeutic agents with unique conditional effector functions and target selectivity (A-Kines). The presentation will review various approaches to the reprogramming of myeloid cells, T cells, and tumour microenvironments, with A-Kines that exhibit exquisite target-cell selectivity.

Cytokines emerged as promising molecules for therapeutic intervention in order to modulate the immune response. However, their often pleiotropic nature, combined with their high potency when administered systemically, restricts their therapeutic applicability. We have generated cytokine mimetics with tailor-made mode-of-actions based on multifunctional antibody derivatives.