Endothelial cells (ECs) play an important gatekeeper function for immune cells. The interaction of perivascular macrophages (PVMs) with tumor ECs affects the entire tumor microenvironment and shapes the immune landscape. Single-cell RNA-sequencing data from human lung tumors identified 200 PVM/EC receptor-ligand target pairs. Based on these new insights and novel in vitro assays to model the complex PVM/EC biology Montis Biosciences is developing therapeutic antibodies against lead targets.

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Immuno-therapy has offered a great contribution to cancer therapy, but the issue of “cold tumours” remains a significant problem. The tumour structure itself can give rise to defence mechanisms that exclude immune system cells. Rather than “forcing the door," RhoVac’s RhoC-based T cell activator, RV001, (currently in Phase IIb and FDA-Fast-Tracked for prostate cancer) targets migrating metastatic cells before they can form metastatic tumours, thus eluding tumour defence lines. On top of the FDA Fast Track Designation in the US, the development of RV001 is also backed financially by the European Innovation Council Horizon 2020 program.  

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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 that impact different types of antibody immunotherapy (direct targeting and immunomodulatory) and how they might be targeted to improve treatment efficacy.

This talk will focus on B cells and their expressed antibodies in the tumour microenvironment, and specifically on B lymphocyte recruitment, lymphoid assembly and class-switching towards distinct immunoglobulin isotype-biased profiles in breast cancer and melanoma. Clonal expansion with specific variable region gene combinations and narrow repertoires and class-switched B lymphocyte lineage traits may favorably associate with outcomes and could help uncover novel biomarkers for patient stratification and novel treatment targets.

TNFR2 is strongly expressed in the immune suppressive tumor microenvironment. We have generated isotype-optimized ligand-blocking, or agonist, antibodies to this T cell co-stimulatory receptor. Anti-TNFR2 mAb eradicated large solid tumors through mechanisms involving intratumoral Treg-depletion and/or CD8+ T cell expansion, alone or in combination with anti-PD-1. Here we discuss the potent anti-tumor activity and mechanism-of-action of anti-TNFR2 mAbs including BI-1808 – a first-in-class anti-TNFR2 antibody for cancer immunotherapy.

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Agents that target solid tumours via CD47 are limited by intrinsic challenges, such as the large systemic target sink and indiscriminate binding of non-tumour cells, leading to increased toxicity. These factors collectively limit the potential safety and efficacy of anti-CD47 antibodies and many other types of anti-tumour antibodies with immune-engaging MOA. LockBody agents directly address these issues by bypassing systemic sinks, minimizing toxicity and maximizing functional activity in the tumour.

Sym024 is an Fc-attenuated human monoclonal antibody that binds to human and cynomolgus monkey CD73 with sub-nanomolar avidity. Sym024 binds to a distinct epitope on the enzyme on the opposite side relative to the catalytic center and potently inhibits the activity of soluble CD73 as well as CD73 expressed on numerous cancer cell lines and primary lymphocytes. Importantly, CD73 inhibition by Sym024 alleviates AMP-mediated inhibition of T cell proliferation and activation. In vitro one-way mixed lymphocyte reaction results demonstrate the utility of combining CD73 inhibition with PD-1 blockade, as Sym024 acts to reverse the immune-suppressive effect of adenosine production, thereby allowing effective T cell activation by an anti-PD-1 antibody (Sym021). Mechanistically, Sym024 inhibits cellular CD73 by direct enzymatic inhibition with moderate shedding or degradation of CD73 in vitro. In preclinical in vivo tumor models, Sym024 effectively inhibits CD73 activity and tumor growth. Sym024 was well tolerated with no observed toxicity in repeat-dose studies in monkeys at dose levels up to 100 mg/kg. Dose-proportional and linear pharmacokinetics (PK) was observed at high dose levels while nonlinear PK became evident at lower exposure levels. Sym024 is currently under clinical investigation.

Activation of CD40+ antigen-presenting cells (APCs) aims at generating anti-tumor T cell responses. So far, dose limitations due to on-target systemic toxicity restrict the amount of systemically administered CD40 agonists that can be delivered to the tumor to activate APCs locally. We developed a fibroblast-activation-protein – a (FAP)-CD40 antibody, which activates CD40 solely in presence of the tumor stromal antigen FAP. FAP-CD40 enables safe administration of higher doses, essential for inducing antitumor immunity.

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Nanofitins are small and robust affinity proteins considered as alternatives to antibodies. These proteins can easily be associated with each other in order to increase avidity or multi-specificity. In the development of anti-tumor strategies, the assembly of Nanofitins with various activities (targeting of receptors / soluble factors, recruitment of immune cells, etc) allows the targeting of multiple pathways involved in cancer progression and aims at the development of an effective anti-tumor response with limited toxicities.

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The ProTECT platform aims to expand the therapeutic window of a multispecific antibodies through tumor-specific activity and enhanced immune modulation in a transferable design. IgV domains of immunomodulatory pairs are appended to N-termini of antibodies to sterically preclude binding to their target tumor-associated-antigen. Upon protease activation, in addition to recovering target binding, a remaining immunomodulatory domain can exert checkpoint modulation/co-stimulation to confer additional synergistic anti-tumor activity. As a proof-of-concept, we show that for an engineered anti-CD3/HER2 bispecific T cell engager, incorporation of the PD-L1/PD-1 ProTECT design creates a more potent, conditionally active, anti-CD3/PD-L1/HER2 trispecific.

We have developed a bispecific antibody targeting CD40 that is able to carry antigens into APCs through a non-covalent high-affinity interaction between the antibody and the antigen. The antigens delivered are embedded in synthetic long peptides (SLP) synthesised with a peptide tag (pTag), a constant short amino acid sequence that the antibody binds to with high affinity, providing a flexible drug candidate. We hereby refer to this novel technology as the Adaptable Drug Affinity Conjugate (ADAC). While traditional Antibody-Drug Conjugates (ADCs), rely on chemical conjugation, limiting their flexibility, we show that the ADAC technology retains CD40 mediated activation of APCs and through receptor internalization deliver the SLPs for antigen-presentation. This technology thus ensures peptide delivery and activation to the same APC for optimal T cell activation and expansion, rather than depend on local antigen shedding from the tumor. The ADAC's flexibility with the affinity interaction with the SLP is a great tool to address the need for individualized cancer vaccine development when sequencing data will guide neoantigen selection and allow for tailored SLP delivery.