Local immunotherapy is attractive to overcome the challenges of toxicity and limited bioavailability observed with systemic delivery of immunotherapies yet elicit systemic immunity. We show that cationic peptides can be deployed as a modular anchor to enhance intratumoral retention and penetration of immune checkpoint inhibitor antibodies in tumor ECM via electrostatic interactions towards improved antitumor efficacy.

9The talk will explain how expansion of peripheral blood gamma delta T cells in the presence of TGF beta enhances the yield and fitness of these cells, leading to an increase in their intrinsic anti-tumour activity. As a result, we are exploring the use of these TGF-beta-educated gamma delta T cells as a potential off-the-shelf CAR T cell strategy, benefitting from this increase in anti-tumour activity together with novel cytokine armouring technologies.

MorphoSys´ CyCAT (Cytotoxic Cell Activation at Tumor) platform is based on novel T cell engagers that become activated after dual-tumor target binding and reassembling of proprietary anti-CD3 VH/VL split domains. To enhance CyCAT potency, a set of formats was developed with different structures and distances between the binding domains that can be freely combined to enable formation of an optimized immunological synapse between the T cell and the tumor cell especially when different target epitopes, membrane distal and proximal, are simultaneously targeted.

We have designed MP0533, the first avidity-driven T cell engager (TCE) targeting three tumor-associated antigens (TAA) on AML cells to ensure potent T cell-mediated killing of malignant cells while sparing healthy cells. MP0533 has been generated by selecting an optimal affinity against CD70, CD123, and CD33, combined with a suitable CD3-binding DARPin and an optimal molecular architecture to allow exceptional efficacy and superior safety profile vs mono-specific TCE approaches.

CD40 agonistic antibodies rely on antigen-presentation for optimal efficacy. The source of antigen can be either from the tumor or by exogenous delivery of antigens. Via the ADAC technology, any synthetically produced peptide can be delivered to dendritic cells for optimal cargo delivery and simultaneous immune activation. This strategy improves efficacy while allowing for a dose reduction, thus also reducing the risk for toxicity.

Imvotamab (IGM-2323) is a bispecific IgM antibody that binds very tightly to CD20 and engages CD3 on T cells. This bispecific IgM shows superior binding to CD20+ cells and out-competes a bivalent anti-CD20 IgG. In vitro, Imvotamab can kill lymphoma cells via CDC and T cell-dependent cellular cytotoxicity. With robust cytotoxicity and low cytokine release, Imvotamab exhibits an improved safety profile compared to bispecific IgGs. Imvotamab is in clinical trials in patients with relapsed/refractory B cell non-Hodgkin lymphoma.

CRS is one of the major safety liabilities associated with T cell engaging therapies in the clinic, including CAR T cells and T cell engagers. A recent screening of FDA-approved kinase inhibitors identified JAK, mTOR, and Src inhibitors as potential candidates for the mitigation of CRS. Here, we present in vitro and in vivo preclinical studies showing the effects of kinase inhibitors on cytokine release and anti-tumor efficacy.

Mablink is building a diversified proprietary pipeline of novel antibody-drug conjugates based on the strong potential of “hydrophobicity masking” concept with orthogonally-embedded chemical modifiers grafted into drug-linker constructs of ADCs to significantly improve their therapeutic index. Non-clinical data collected so far in all proprietary ADC candidate programs represent a broad proof-of-concept and non-clinical validation of hydrophilic monodisperse polysarcosine-based ADCs in targeting of both liquid and solid tumors, illustrating its impact on physicochemical and pharmacological properties of these conjugates.