This presentation will describe preclinical data from Regeneron’s new clinical approaches to enhancing anti-tumor efficacy of T cells, focusing on the combination of co-stimulatory bispecific antibodies with checkpoint blockade and T cell redirecting bispecifics. In addition, data from new classes of T cell-targeted enhancement strategies will be discussed, including preclinical data from our PD-1 targeted receptor masked IL2 that has entered clinical development.

T cell engaging bispecific antibodies targeting CD3 have had tremendous success in treating hematologic tumors but have shown limited efficacy in solid tumors. Employing safe and tunable bispecific antibodies for a wider variety of immune stimulating receptors may help address solid tumor-related challenges. Here, we describe bispecific platforms developed at Rondo Therapeutics and highlight progress on our lead program, RNDO-564, a CD28 x Nectin-4 bispecific antibody for treatment of metastatic bladder cancer.

Xencor has developed a versatile platform for the creation of bispecific antibodies, with a particular focus on T cell engagers. We’ll discuss application of the platform to solid tumors as well as for the depletion of pathogenic CD20-positive or CD19-positive B cells in autoimmune diseases.

Bispecifics targeting 4-1BB or CD28 have emerged in oncology to unlock the full potential of T cell bispecifics (TCBs), aiming for chemo-free treatments. The emerging clinical and biomarker data from Roche's Phase 1 trials combining co-stimulatory bispecifics with TCBs in hematologic malignancies show compelling safety and efficacy profiles, evidence of costimulatory action, and enhanced memory T cell responses, paving the way for novel and innovative combination therapies.

Immunocore has developed ImmTAAI, a new class of bispecific protein therapeutic designed to deliver targeted immunomodulation to treat autoimmune diseases. The effector domain comprises an agonistic anti-PD-1 VHH, which is biologically active only when target-bound and does not compete with natural ligand (PD-L1/L2), providing a wide therapeutic index. Using this targeted approach we have developed two distinct bispecific molecules, one which specifically targets pancreatic beta cells to treat Type I Diabetes (T1D) and another which specifically binds an HLA unrestricted APC target in skin, to treat inflammatory skin diseases.

Multispecific antibodies hold significant advantages for the treatment of patients with inflammatory diseases. We will share important design principles for multispecific antibody construction and considerations for target selection in an increasingly crowded space. We will also present the advantages and some key examples of Numab's platform for the generation of best-in-class multispecific antibodies.

Serine proteases kallikreins KLK5 and KLK7 are critical for maintaining skin barrier function. Excessive KLK activities can lead to Netherton syndrome and atopic dermatitis. Our study demonstrated that combined treatment with inhibitory anti-mKLK5 and anti-mKLK7 antibodies improves skin integrity and reduces inflammation in mouse NS and AD models. We further generated a humanized bispecific anti-KLK5/7 inhibitory antibody, presenting a promising therapy for clinical development in NS and other inflammatory dermatoses.

Mast cells (MCs) are a distinctive hematopoietic effector cell population that are sentinels of innate immunity and play an important role in orchestrating immune responses at barrier tissues. While well-known for their role in IgE-dependent type 1 hypersensitivity that underlies anaphylaxis and other acute manifestations of atopy, MCs are also associated with several other disease states. KIT, the protein of the c-Kit protooncogene, and its ligand stem cell factor (SCF) are central regulators of MC biology impacting differentiation, migration, maturation, survival, and activation. Blocking the KIT pathway offers the ability to deplete MCs and in doing so alleviate their pathogenic biology. Since the KIT/SCF axis regulates several stem cell populations, precise targeting of the pathway on MCs is required to bypass the toxicity issues associated with KIT/SCF blockade. In this presentation we will cover the strategy to develop SAB01, a conditionally active bi-specific antibody which offers the potential for a safer approach to treating MC driven diseases.

Multispecific CD3 Switch-DARPin T-cell engagers aim to overcome current therapeutic challenges, like lack of universal tumor target antigens (TAAs) and poor efficacy/toxicity profiles. Switch DARPins allow masking a T cell-engaging DARPin until a defined target or combination of targets is encountered on the surface of target cells. The increased tumor specificity allows for safely adding a co-stimulatory function for potent and sustained anti-tumor T cell responses and expanding the targetable TAA field.

EpCAM is a very attractive target since it is expressed in a wide variety of tumors. However, it is also widely expressed on normal tissues, making it a challenging target for traditional cancer therapies. BA3182 is a conditionally active T cell engager (TCE) targeting EpCAM. The Conditionally Active Biologic (CAB) technology enables selective binding to the EpCAM and CD3 targets only in the tumor microenvironment. Preclinical, as well as initial clinical data will be discussed.

XPAT proteins are conditionally active TCEs designed to exploit the dysregulated protease activity in tumors. Preclinically, XPAT proteins demonstrated 1) strong masking of in vitro cytotoxicity by approximately 4 logs; 2) potent in vivo efficacy at doses similar to the efficacious doses of unmasked TCE controls; and 3) increased MTDs in NHP by greater than 100-fold. Clinical trials of XPAT proteins targeting HER2 and PSMA are currently ongoing.