Oncogenic mutants of intracellular proteins are attractive sources of tumor-specific neoantigens presented by MHC. However, recognizing minimal differences between oncomutations and their wild-type counterparts is challenging. We have established the HapImmune technology that exploits covalent inhibitors to create distinct neoantigens presented by MHC that can be targeted with antibodies. HapImmune bispecific antibodies selectively and potently kill drug-treated but drug-resistant cancer cells, thereby uniting targeted and immune therapies.

Bispecific T cell engagers represent a highly effective immunotherapy for the treatment of hematologic malignancies. However, blinatumomab, a bispecific T cell engager of CD3/CD19, has disadvantages in the clinical setting due to the adverse pharmacokinetics (short elimination half-life), neurotoxicity, and cytokine release syndrome. JY108 was prepared by a patented pegylation bispecific linker technology, which could address the limitations of current therapeutic approaches.

MSLN is expressed on about 30% of human cancers and is a popular target for antibody-based therapies. MSLN is shed from cancer cells, and levels are high inside tumors preventing antibodies from reaching and killing tumor cells. Mab15B6 binds to cell-bound MSLN, but not to its shed forms; other anti-MSLN antibodies bind to both. Bispecific T cell engagers with 15B6 are very cytotoxic to cell lines and have high anti-tumor activity in mice. In mice engineered to express human mesothelin, a single IV dose causes complete remission of tumors.

Bispecifics mimicking costimulatory signal 2 enhance T cells activation and anti-tumor efficacy, when combined with PD1 checkpoint inhibitors, despite some tumors remaining unresponsive. EGFR over-expression in many tumors is a key immunotherapy target, yet faces resistance and toxicity. EGFRxCD28 bispecifics combined with anti-PD-1 enhance tumor response and immune memory without the toxicity of CD28 superagonists in mouse and primate models, offering a promising, well-tolerated combination therapy.

• Challenges and solutions in bi- and multi-specific antibody design
• CMC considerations for bi- and multi-specifics
• Advancements in solid tumors and future directions​​

T cell engagers are rapidly transforming cancer care. Adapting these biotherapeutics to target the massive intracellular proteome has been a critical goal for improving cancer treatment—but it is challenging due to low cell-surface density antigen presentation. Here, we evaluate the interplay of geometry and valency on T cell engager bioactivity and demonstrate that geometry plays an important role in efficiently targeting low density cell-surface pMHC, rather than avidity.

A simple method was developed for the site-specific, covalent attachment of T cell-redirecting domains to any Immunoglobulin G (IgG) antibody. By labeling antibodies isolated from immunocompetent mice inoculated with NALM-6 leukemia cells, we show it is possible to generate T cell-redirecting autoantibodies that act as an effective therapeutic against NALM-6 tumors. The incorporation of autoantibodies into a bispecific antibody format presents a new paradigm in personalized cancer treatment.

T cell engagers (TCEs) have had limited success against solid tumours due to drug design parameters that have resulted in a narrow therapeutic window, and challenges associated with the biology of the tumor that play a role in treatment resistance and failure. To address these challenges, we have engineered TCEs with enhanced antitumor activity, improved safety and differentiated mechanisms of action. Designed to improve the therapeutic window, ZW171, a novel 2+1 T-cell targeting bispecific antibody for mesothelin (MSLN)-expressing cancers. To improve T cell functionality and antitumor responses in solid tumors with limited intratumoral T cell availability and poor T cell function, our TriTCE Co-stim platform was designed with integrated and conditional CD28 co-stimulation.

T cell engaging bispecific antibodies have had tremendous success in treating hematologic tumors but have shown limited efficacy in solid tumors. Alternative strategies for engaging the immune system employing safe and tunable bispecific antibodies are needed to overcome the challenges of solid tumors. Co-stimulatory bispecific antibodies have the potential to drive durable and robust anti-tumor responses either as single agents or in combination with CD3-engaging antibodies. In this presentation, we describe the bispecific platforms developed at Rondo Therapeutics and how we plan to use these to treat solid tumors in the clinic. We highlight progress on our lead program, RNDO-564, a CD28 x Nectin-4 bispecific antibody for treatment of metastatic bladder cancer.

The development of conventional T cell engagers (TCEs) for solid tumors presents two challenges: the risk of “on-target, off-tumor toxicity” and T cell dysfunction associated with signal 1-dependent T cell activation. We generated SAIL66, a tri-specific antibody against CLDN6/CD3/CD137. By applying our proprietary next-generation TCE technology (Dual-Ig), SAIL66 activates both signal 1 and signal 2, therefore appropriately activating T cells and demonstrating more potent anti-tumor effects than conventional TCEs.

ABBV-184, a novel TCR/anti-CD3 bispecific composed of a highly selective soluble TCR that binds a peptide derived from the oncogene survivin (BIRC5) bound to the Class I MHC allele human leukocyte antigen (HLA)-A2:01 expressed on tumor cells, and a specific binder to the CD3 receptor on T cells. ABBV-184 is an attractive clinical candidate for the treatment of patients with AML and NSCLC.

Bispecific immunotherapeutic biologics offer tremendous potential to improve clinical efficacy and safety by targeting two different antigens in immune and tumor cells. However, the clinical use of these immunotherapies is limited due to immune-related adverse events (irAEs) caused by a hyper-activated immune system. In this presentation, we will provide an in-depth analysis of the safety challenges associated with bispecific immunotherapies and the rapidly rising use of antibody-drug conjugates, offering a comprehensive understanding of these complex issues.

We engineered a targeted cytokine, PD1/IL15 TaCk, combining an anti-PD-1 antibody with engineered IL-15. This construct delivers IL-15 signaling selectively to PD-1-expressing lymphocytes. Using the MABEL approach and studying PK/PD effects in cynomolgus monkeys, we determined the first-in-human (FIH) dose (0.003 mg/kg) and dosing frequency (Q3W) for clinical trials. Our findings shed light on the complex PK/PD dynamics of PD1/IL15 TaCk, informing dose selection and dosing frequency for clinical evaluation.