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.

Dual-specific antibodies show promise as enhanced therapeutics, but the discovery of rare, cross-reactive, and developable antibody clones remains a significant challenge. To address this, we integrated three proprietary platforms—AlphaPan (phage display), AlphaSeq (synthetic biology), and AlphaBind (ML-based modeling)—into a unified workflow designed to accelerate dual-specific antibody engineering. This modular workflow generates high-affinity stable and developable clones that can be readily adapted for a wide range of targets.

• Increasing therapeutic windows (tuning potencies, better targeting, masking, etc.)
• Combining CD3 and co-stim signaling (bispecific combos vs. trispecifics)
• Challenges with preclinical models for efficacy and tox
• Indication selection + monotherapies vs. combo therapies​

T cell engagers (TCEs) are effective cancer therapies but systemic toxicity and limited specificity, restrict their full potential. Several masking approaches for TCEs have been designed to specifically be “unmasked” in the tumor microenvironment, with the aim of increasing their therapeutic index. Molecular Partners’ logic-gated CD3 Switch-DARPin enables reversible, tumor-specific T cell activation in the presence of a defined combination of tumor-associated antigens (TAAs).

• What are the patient's remaining needs?
• What are the advantages and disadvantages of current masking methods?
• What criteria should everyone aim for, and what needs to be established to declare success?
• Should TCEs’ masking strategies be customized to address TME heterogeneity?

The bispecific platform (ImmTAX), initially focused on oncology, was adapted to address other disease areas. For HIV, molecules were designed to eliminate the proviruses reservoir that is the main barrier to a functional cure. For autoimmune diseases, bispecifics encompassing a tissue targeting-arm and PD-1 agonist were designed to protect normal cells from T cell destruction. Successful programs require deep understanding of underlying disease biology coupled with innovative protein engineering.

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.

T lymphocyte redirection has been addressed by two main approaches: systemic infusion of bispecific T cell engagers (TCE) that bind simultaneously to the CD3 and to a tumor-associated  antigen (TAA), and adoptive transfer of genetically modified T cells expressing TAA-specific chimeric antigen receptors (CARs). We have developed a novel strategy based on in situ secretion of TCE antibodies by engineered T cells, termed STAb-T, which aims to combine active trafficking of adoptively transferred T cells to the tumor with polyclonal T cell recruitment by locally secreted TCEs. Adoptive transfer of STAb-T cells has demonstrated potent antitumor activity in vivo in solid and hematological tumor models.