Main Conference Day 3Wednesday, 16 December 2026 - PT (Pacific Time, GMT-08:00)

The protective L9 antibody preferentially recognizes the ‘NVDP’ minor repeat motif in Plasmodium falciparumcircumsporozoite protein (CSP), with lower affinity to the ‘NANP’ major repeat motif. However, strain variation in NVDP minor repeat number and spacing may limit breadth across strains. Using directed evolution and yeast display, we discovered a panel of affinity-improved L9 variants. Among these, L9_yd19 conferred improved protection against diverse chimeric CSP variants while preserving potency against the more common strain 3D7’s CSP architecture. Cryo-EM revealed distinct dual homotypic antibody interfaces, with the new interface outlining a structural mechanism to form higher-order Fab assemblies and broaden protection across diverse PfCSP repeat architectures.

This talk will present an integrated nanobody engineering platform spanning serum proteomics, AF3-TurboAb–enabled antibody-antigen modeling, and multivalent biologic design. I will highlight how scalable structural prediction and interface analysis guide programmable nanobody therapeutics for infectious disease, toxin neutralization, and cancer precision medicine.

Engineering a native-like 1+1 bispecific antibody requires correct heavy-light chain pairing of two distinct Fab domains. To minimize the production of mispaired Fabs, we developed orthogonal heavy-light chain pairs via interface engineering. These Fab domains, termed XenLock™ Fabs, enabled the generation of multiple native-like 1+1 bispecific antibodies, including XmAb412, a novel effector-less bispecific antibody incorporating Xtend half-life extension technology that simultaneously blocks signaling stimulated by IL23 and TL1A.

T cell engagers (TCE) for solid tumors are often limited by off-tumor toxicity and T-cell exhaustion. We engineered a logic-gated Switch-DARPin TCE which pairs a masked CD3 module with CD2 co-stimulation, restricting its activation only to cells co-expressing MSLN and EpCAM. This AND-gate design improves tumor selectivity while sustaining T-cell proliferation and activity, offering a strategy for more effective bispecific TCEs against EpCAM/MSLN-positive solid cancers with favorable safety profile.

Monoclonal antibodies act through Fc receptor–dependent and –independent mechanisms, all of which are strongly influenced by the nanoscale organization of antibodies and receptors on the cell surface. Here, we develop a method to directly visualize and quantify receptor–antibody complexes in three dimensions within intact cell membranes. Applying this approach, we uncover distinct nanoscale organizational patterns of Type I and Type II anti-CD20 antibodies, revealing how spatial arrangement governs antibody function and provides principles for therapeutic mechanism and design.

Native immune responses are polyclonal in nature, yet most therapeutic antibodies to date are monoclonal. One limiting factor for the development of therapeutic polyclonal antibodies is the “chain-association issue” (incorrect chain pairing during co-expression of multiple antibodies). Here, we describe the generation of mutual exclusive CH3 interfaces to ensure correct H:H chain pairing. In combination with strategies addressing correct H:L chain pairing, this enabled the production of polyclonal antibody mixtures.