In this presentation, a novel peptide linker technology will be introduced that enables site-specific linker-payload conjugation to native antibodies in one step, without the need for any antibody engineering. The resulting ADCs show remarkable in vivo stability and antibody-like PK exposure. ADCs carrying topoisomerase-1 inhibitors at various drug-load ratios were generated which showed excellent efficacies in multiple head-to-head studies vs. trastuzumab deruxtecan (T-DXd). In particular, an ADC carrying two different Topo-1 payloads showed superior efficacy vs. T-DXd in a challenging, moderate HER2-expressing animal model. These data highlight the potential of this peptide linker-payload platform to generate stable ADCs that have a maximized payload exposure to tumours.

Fcab-Drug Conjugates are a novel ADC format carrying an Fc antigen binding fragment (Fcab) as targeting scaffold instead of an IgG antibody. The combination of Fcabs’ small size, antigen binding capabilities, and relatively long half-life makes them a promising scaffold for the generation of drug conjugates with improved tissue penetration capabilities compared to classical IgG-based ADCs. This talk covers the concept and format exploration data.

ELU001 is a C'Dot Drug Conjugate (CDC), a targeted ultra-small (~6nm diameter) nanoparticle composed of a silica core, a layer of short PEG chains conjugated to ~21 exatecan payload and ~13 folic acid targeting moieties. The safety and efficacy results of Elucida’s first in human study with ELU001 will be presented.

This presentation will discuss the nonclinical pharmacology of the MET-targeting ADC BYON3521.

Advances in T-cell-based immunotherapies resulted in unprecedented clinical responses. Nevertheless, most patients remain unresponsive to immunotherapy. Bispecific antibodies that bind to tumor targets and cytotoxic T-cells are promising immunotherapies. However, providing co-stimulatory signals may improve T-cell responses. Herein, we develop a trispecific antibody targeting canine CD20, CD3 and CD28 for improved activation and sustained T-cell response against canine non-Hodgkin lymphoma.

ABL102, a novel bispecific antibody targeting ROR1 and 4-1BB, activates 4-1BB in tumor microenvironment. ABL102 exhibited potent anti-tumor activity across several tumor types and induced protective memory. ABL102 induced immune cell infiltration and Treg depletion in tumors without triggering systemic immune response. ABL102 was well tolerated and safe in the NHP toxicity study. These results strongly suggest that ABL102 is a promising therapeutic for ROR1-positive cancer patients.

Intracellular antibodies are a starting point as inhibitors via design to block protein-protein interactions or to carry effector functions. Expressing fusions of intracellular antibodies with E3 ligase creates biodegraders to eliminate target proteins, or with procaspases to cause antigen-dependent cell death. The targeting LMO2 and mutant RAS is POC for intracellular antibodies as drugs per se.

Antibody therapy based on glycan targets remains attractive. We will present preclinical results from reformatting these antibodies to T cell redirecting bispecifics, ADC, as well as their potential for CAR therapy; showcasing their versatility. Combination therapy may be warranted for optimising their efficacy towards solid tumours. 

We have developed mutually-dependent IgG antibody combinations engineered to selectively act on cells co-expressing two antigens. Genmab’s HexElect technology is based on Fc-domain engineered IgG antibody pairs that act as Bio-Logic AND gates selectively activated after hetero-oligomerization. Functional activation of complement or signaling by HexElect antibody pairs was stringently dependent on the presence of two targets co-expressed at the same cell surface. HexElect technology may enable access to an untapped, combinatorial target space for the generation of antibody therapeutics that exhibit both selectivity and potency.

SNS-101 is a conditionally active anti-VISTA antibody designed to relieve T cell suppression driven by the VISTA-PSGL-1 immune checkpoint within the acidic tumor-microenvironment, currently in a Phase I study (NCT05864144). SNS-101 displayed strong anti-tumor activity in syngeneic tumor models as both monotherapy and in combination with PD-1 blockade. pH-selective target engagement resulted in a significantly improved safety and pharmacokinetic profile in non-human primates, suggesting SNS-101 may overcome prior hurdles of anti-VISTA biologics. 

STA551 is a clinically investigated anti-CD137 agonist antibody that activates immune cells only in the presence of extracellular ATP. Previous study showed a synergistic efficacy of combining STA551 with anti-PD-L1 antibody. Using scRNA-seq, I tried to elucidate the mechanism and found this effect was due to an increase in activated T cells and a decrease in exhausted T cells. I would like to discuss the detail mechanism of action of STA551.

Novel NK cell engagers (NKCE) based on NKp30-targeting single domain antibodies (sdAb) that redirect the cytotoxic potential of NK cells towards EGFR-expressing tumor cells were generated. The impact of crucial parameters such as sdAb location, binding valencies, the targeted epitope on NKp30 as well as the overall antibody architecture on the redirection capacity were investigated. Our findings reveal novel insights for the engineering of potent NKCE triggering the NKp30 axis.