AAV vectors are now used in multiple FDA-approved gene therapies and hold tremendous promise as a modality for treating genetic diseases. However, the application of these vectors remains constrained by delivery inefficiencies, dose-limiting adverse effects, and manufacturing challenges. In this talk, I will discuss our ongoing efforts to expand the impact of gene therapy through the development of AAV capsids with novel capabilities using data-driven protein engineering methods.

We will focus on clinical treatment of pediatric patients with hematological malignancies using engineered cellular therapies. An overview of the current state-of-the art will be presented, with specific highlights on the therapeutic issues. We will add our data on development and testing of engineered cell products against AML.

We identified an IgG1 and a VH-Fc which bound with high affinity/avidity to SARS-CoV-2 S glycoprotein and mutants found in patients. They potently and specifically neutralized SARS-CoV-2 in hACE2 expressing transgenic mice and hamsters as well as mouse ACE2 adapted SARS-CoV-2 in wide type BALB/c mice at doses as low as 2 mg/kg which in combination with their good developability suggests their potential use for prophylaxis and therapy of COVID-19.

This year marks the 45th anniversary of the first publication on monoclonal antibodies. This presentation provides insight to how far we have come in that time, presenting an overview of current, publicly available clinical stage antibodies, Fc fusion proteins, and chimeric antigen receptor (CAR) constructs, the combination of which there are currently over 1,000 examples. Different strategies for addressing the 300-plus unique target antigens will be compared and contrasted.

The ORBIT is a paradigm-shift platform in academic institute dedicated to discover and develop therapeutic biologics and cell therapy. We want to harness our strengths on clinical science and basic cancer research to identify novel targets and translate such scientific knowledge into first-in-class therapeutic antibodies, and quickly advance these agents into clinical trials. Examples will be discussed on how we could accelerate early discovery into clinical development.

PCSK9 inhibitors represent the third proven class of medications (following statins and ezetimibe) to reduce LDL-cholesterol and prevent cardiovascular events. The first two PCSK9 inhibitors approved for clinical use were monoclonal antibodies, but other approaches, including antisense oligonucleotides and small interfering RNAs, have been studied in humans. Mimetic peptides, LDL-receptor antagonists, small molecules, vaccines, and gene silencing approaches are in earlier stages of development.

AlivaMab Discovery Services produces low picomolar, neutralizing, development-ready human antibodies against even toxic targets in exceptionally fast timelines. Combining Ablexis' AlivaMab Mouse with ADS' proprietary AMMPD immunizations and direct-to-function screening puts projects on the fastest, most de-risked path from discovery through development and to market.

Two cell therapy and T cell engager technologies are advancing for diverse cancer indications. We developed novel proteins designed to complement and extend the functionality of cell therapeutics called bridging proteins. These can be considered CAR-T cell engagers by MOA. We present examples of the creation and evaluation of these proteins, for delivery to the patient as a biologic for injection or for delivery within the CAR T cell itself.

The law is in chaos with respect to the patentability of medical diagnostics and therapies, DNA, RNA, and proteins. The PTO and courts are acting inconsistently. Last year Congress seemed close to passing clarifying legislation, but that effort died. This presentation addresses such questions as: Are existing patents that seem to restrict research really valid? Are new therapies likely to be patentable? If not, can they attract necessary capital?

CD20 is a B cell marker of unknown function targeted by monoclonal antibodies (such as Rituximab) for the treatment of B cell disorders. We obtained a structure of CD20 in complex with Rituximab, revealing CD20 as a dimer bound by two Fabs; each Fab engages a composite epitope and an homotypic Fab:Fab interface. Our data suggest that Rituximab crosslinks CD20 into circular assemblies, leading to a model for complement recruitment.

Integral membrane proteins represent a major class of therapeutic targets currently underserved by antibody-based drugs. Using a combination of immunization, single B cell isolation, and yeast-based cloning and expression, we have developed a high-throughput method to discover antigen-specific antibodies to a variety of membrane protein target classes. Here, we demonstrate the efficient and large-scale isolation of high-affinity antibodies against membrane protein targets, including CCR8, a class-A GPCR.

Successful biologic discovery requires development of comprehensive screening funnel. Introduction of functional assays early in the screening process enables effective selection of biologics with a desired mode of action and improves understanding of drug biology. This presentation will highlight benefits of the early implementation of functional assays into biologics screening funnel.