We describe the 1.9Ã… resolution crystal structure of anti-CD3 single domain antibody ADI-98214, which is equipotent to UCHT1 when paired with IgG or TCR modalities but greatly simplifies bi- and multispecific assembly. The structure reveals a novel binding mode that overlaps with but is distinct from UCHT1 and informs further tuning to optimize affinity, with the aim of advancing the next generation of T-cell engagers.

CD3-targeting T-cell engagers show significant clinical benefit in hematological malignancies, but limited efficacy in treating solid tumors partially due to the immunosuppressive TME. To overcome this challenge, we develop bispecific antibodies that activate the CD28 costimulatory receptor when bound to a tumor-associated antigen for the treatment of solid tumors. Here, we describe our lead molecule RNDO-564, a potency optimized CD28 x Nectin-4 bsAb for the treatment of metastatic bladder cancer.

We engineered a trispecific T cell engager platform with integrated CD28 co-stimulation (TriTCE Co-Stim) that provides a differentiated target-dependent antitumor activity and safety profile facilitated by conditional CD28 co-stimulation, requiring CD3 engagement and obligate cis T cell binding resulting in no target-independent T cell activation or T cell-T cell bridging. Here, we present transferability of the TriTCE Co-Stim platform to improve anti-tumor activity and specificity via avidity-driven multivalent, logic-gated, and TCR mimetic (TCRm) targeting approaches.

The presence of multispecific modalities is rapidly increasing in clinical trials.  Among these complex modalities are T cell engagers (TCEs), a category of T cell-retargeting immunotherapy transforming clinical cancer care. The application of TCEs has in part been limited by challenges including on-target, off-tumor toxicity and poor therapeutic index (TI) linked to aberrant cytokine release. To overcome this challenge, we have designed the TriMab, a dual-targeting TCE with improved TI.

Natural killer (NK) cells have been shown to have a role in the control of acute myeloid leukemia (AML), but they are limited in their efficacy by lack of antigen specificity. To address this issue we have developed the Tri-specific Killer Engager (TriKE) platform, which imbues NK cells with antigen specificity through anti-CD16 and anti-tumor associated antigen (CD33, in this case) engager arms. It also drives their expansion through an IL-15 moiety in the middle of the molecule. Here we will discuss clinical findings from two generations of CD33 targeting TriKEs and ongoing efforts to develop next-generation molecules.

ROSE12 is a novel anti-CTLA4 antibody that activates in response to high concentrations of extracellular ATP in the tumor microenvironment. In addition, affinity of ROSE12 against FcγRs is increased by asymmetric Fc. Therefore, ROSE12 shows very strong ADCC activity. ROSE12 also selectively depleted intratumoral Tregs, demonstrating anti-tumor effects without inducing systemic immune activation in mouse models. Currently, ROSE12 is undergoing a Phase I clinical study.

The therapeutic potential of T Cell Engagers (TCE) has been limited by a narrow safety window, with excess cytokine release and on-target toxicity limiting their clinical usefulness. Our Tumor-Microenvironment Activated Therapeutics (T-MATE) technology overcomes these challenges by utilizing a pH-dependent conformational switch. This innovative mechanism attenuates TCE activity at physiological pH while preserving full potency within the tumor microenvironment, enabling a new class of safe and effective T cell engagers.

EvolveImmune has developed the EVOLVE platform by integrating CD2 costimulation with precisely tuned CD3 affinity to sustain T cell effector function and decrease target-independent cytokine release. EVOLVE104 targets not only CD3 and CD2 on the T cell but also ULBP2/5/6 on tumor cells of which there is enriched expression in squamous-cell tumors and urothelial cancer. EVOLVE104 is now in the clinic for the treatment of these solid-tumor indications.

Antibody humanization is a critical strategy in the development of therapeutic antibodies, aimed at reducing immunogenicity while preserving antigen specificity and affinity. This presentation showcases LifeArc's case studies on the humanization of monoclonal antibodies (mAbs), highlighting their progression to licensed candidates and clinical trials. We will discuss various antibody engineering techniques employed in humanization, including complementarity-determining region (CDR) grafting, framework region modification, and de novo design. By integrating these methodologies, we enhance the safety profiles of therapeutic antibodies, maintain their functional characteristics, increase human content, reduce immunogenicity, and improve developability.

We are developing various types of multifunctional cell-engager modalities that harness molecular cooperativity and induced-proximity mechanisms to modulate immune-cell connections and functions with a high level of precision. These include in-cis and in-trans acting molecules that encode engineered cytokines with on-target localized effector functions. Several such modalities, including myeloid, T and NK cell engagers, their cancer-immunity cycle-regulatory activities, and potential as novel immunotherapies will be discussed.

TAVO412 is a humanized trispecific EGFR x cMET x VEGF antibody with the potential to control abnormal EGFR signaling, dysfunctional cMET activation, and VEGF-induced angiogenesis which are responsible for the growth and metastasis in difficult-to-treat solid tumors. We highlight the clinical Phase 1 execution to determine the safety and tolerability, define the MTD/RP2D, and assess preliminary efficacy in patients with advanced solid tumors who progressed on prior standard-of-care therapies. We present where TAVO412 has clinical responses in esophageal, colorectal, and lung cancers.

As multispecific immune-engagers move from hematologic cancers into the solid tumor space, clinicians need practical frameworks to explain, monitor, and support these therapies in real-world patients. This talk explores off-the-shelf alternatives to CAR T therapy from the bedside perspective, integrating tumor microenvironment insights, patient safety, and shared decision-making. Attendees will learn how integrative oncology can help translate complex science into meaningful, accessible care.