The anti-tumor efficacy of T Cell Engaging bispecific antibodies (BiAbs) relies on signaling through CD3 without co-stimulation and is impaired by inhibitory co-receptor signaling. Pairs of T cell-directed BiAbs (“Simultaneous Multiple Interaction T-Cell Engaging [SMITE] bispecifics”), which engage cancer-associated antigen(s) and provide CD28 co-stimulation, improve BiAb efficacy in a tumor cell-dependent fashion in vitro in preclinical tumor models. As shown with PD-L1 as example, SMITE bispecifics can transform checkpoint inhibition into T cell activation to overcome BiAb resistance.

We have generated tumor-targeted Fc-free trimerbodies targeting a tumor-associated antigen, such as EGFR or CEA, and 4-1BB in an agonistic manner. Both trimerbodies were potent co-stimulators in vitro and showed enhanced tumor penetration and powerful anti-tumor activity in vivo, while alleviating liver toxicities that are associated with IgG-based 4-1BB agonists. These results promote the use of the non-canonical trimerbodies for safe and effective costimulatory strategies in cancer immunotherapy.

T-cell activation is initiated upon binding of the T-Cell Receptor (TCR)/CD3 complex to peptide-MHC complexes (“signal 1”); activation is then enhanced by engagement of a second “co-stimulatory” receptor, such as the CD28 receptor on T-cells binding to its cognate ligand(s) on the target cell (“signal 2”). However, tumors may evade the immune system often by downregulating one or both of these signals 1 and 2. We developed a class of bispecific antibodies that mimic signal 2, by bridging a second TSA to a co-stimulatory receptor (CD28) on T-cells. Combining this novel class of co-stimulatory bispecific antibodies with PD-1 mAb or the emerging class of TSAxCD3 bispecifics may provide well-tolerated, “off-the-shelf” antibody therapies with potentially enhanced anti-tumor efficacy.

Our unique platform technology called PUREfrex is a fully reconstituted (or rebuilt) cell-free protein expression system. PUREfrex can effectively express scFv, Fab and full IgG as well, which is useful for high throughput screening. In addition to that, we established robust ribosome display with customized PUREfrex called PUREfrexRD, which has great advantage in screening of highly diversified library and developing new antibodies or cyclic peptides.

LAVA is developing a bispecific antibody T cell engager platform that leverages the unique qualities of γδ effector T cells. LAVA’s bispecific γδ T cell engagers have been selected to create a wide therapeutic window with high activity against tumor cells whilst leaving healthy cells unharmed. LAVA’s lead program will enter the clinic in Q1 2021. Recent preclinical development data including potency, mechanism of action and safety will be discussed.

This presentation will describe the challenges solid tumors impose upon cell therapies and how myeloid cells (monocytes and macrophages) may overcome these barriers. The CAR-M concept will be described, and a preclinical dataset that describes this novel immunotherapy in depth will be presented.  

My talk will describe how we use various bispecific antibodies, engineered to enter the brain via receptor-mediated transcytosis, to visualize and quantify amyloid-beta pathology in the brain of living mice, using PET and SPECT imaging. We also use these imaging techniques in the context of amyloid-beta directed therapy, either to quantify the effect of treatment or to localize therapeutic antibody in the brain over time.

MCLA-129 is a full-length, IgG Biclonics® binding to EGFR and c-MET, capable of overcoming c-MET-dependent EGFR TKI resistance mechanisms following ligand-induced signaling. MCLA-129 is glycoengineered to enhance its Fc mediated ADCC and ADCP activity, thus allowing it to inhibit tumor growth independent of EGFR or c-MET signaling.  MCLA-129 holds promise as a potential treatment option for NSCLC and other solid tumors.

Avid binding of multi-specific antibodies can confer desirable therapeutic properties, such as increased specificity to target cells. However, the design requirements and experimental interpretation are often counterintuitive. Mechanistic models provide clarity to guide development decisions (single-arm affinities, dosing) for desired functionality.

PET imaging with 89Zr-labeled antibodies is a non-invasive way to assess target engagement in vivo. Amivantamab, a bispecific antibody that targets EGFR and c-MET was developed as a companion PET imaging agent by radiolabeling with 89Zr. A comprehensive characterization of 89Zr-amivantamab in preclinical models of triple negative breast cancer will be discussed.