Rapid Selection Of High-Value Internalizing Binders For Targeted Therapeutics

SUMMARY

Lentiviral display platform engineered to directly select and enrich antibodies based on their ability to induce receptor-mediated endocytosis, thereby streamlining the discovery of highly internalizing candidates for targeted therapies

The Unmet Need: Efficient discovery platforms that directly select internalizing antibodies for advanced targeted therapies

• The development of monoclonal antibody therapeutics has revolutionized targeted treatments for cancer, autoimmune, and infectious diseases in recent decades. However, clinical success increasingly depends on identifying antibodies capable of efficient cellular internalization- a critical requirement for modalities like antibody-drug conjugates, targeted gene delivery, and CAR therapies.

• Traditional selection methods (such as hybridoma or phage/yeast display) focus primarily on affinity and specificity, often overlooking internalization potential. As a result, late-stage failures and costly development delays frequently arise from insufficient functional screening. Addressing this gap, high-throughput strategies that select for internalizing antibodies can accelerate discovery and improve translational success in advanced biologic therapies.

The Proposed Solution: Engineered lentiviral display to directly select antibodies (including VHHs/Nbs) for productive receptor internalization essential for targeted therapies

• The faculty inventor developed a novel antibody discovery platform that leverages lentiviral display and built-in selection for receptor-mediated endocytosis. This system enables direct enrichment of antibody binders (including single-domain VHH/Nbs) that both bind their targets and are efficiently internalized by live mammalian cells. Unlike conventional phage or yeast display, which primarily select for affinity and specificity, this technology offers a “function-first” approach—identifying antibodies validated to deliver real payloads (e.g., cytotoxic drugs, gene therapies, radioconjugates) inside disease-relevant cells.

• By genetically linking each displayed antibody to the viral genome, the method ensures true genotype-phenotype coupling and supports high-throughput screening. Iterative rounds of selection favor antibodies with the highest internalizing potential, making the platform particularly effective for antibody-drug conjugates (ADCs), antibody-radionuclide conjugates (ARCs), and viral/particle-mediated gene or RNA delivery systems.

ADVANTAGES

ADVANTAGES

• Direct functional selection for rapid, productive internalization (not just binding)

• Enables discovery of highly developable antibody candidates suitable for complex targeted therapies

• Genotype-phenotype linkage streamlines hit identification and downstream developability profiling

• Broadly applicable to multiple receptor, disease, and payload classes

• Reduces time and cost associated with downstream developability/efficacy failures

APPLICATIONS

• Antibody-drug conjugate (ADC), antibody-radionuclide conjugate (ARC) pipeline acceleration

• Optimized selection of CAR-T/CAR-NK and bispecific lead antibodies

• Discovery of internalizing antibodies for targeted viral/gene delivery (e.g., reprogrammed lentiviral, AAV platforms)

• Mammalian display follow-on for high-throughput internalizer enrichment after phage/yeast triage

• Data showing >3–5x enrichment of validated internalizers over state-of-art phage/yeast methods