Despite the extraordinary success of CAR T-cell therapy in hematopoietic cancer, challenges still remain such as lack of durable responses in > 50% of patients and the loss of target antigens can result in loss of transient responses. Moreover, responses to CARTs in solid tumors has been very disappointing. Outcomes have been hampered by factors such as loss of antigen expression, scarcity of tumor-restricted antigens, poor T cell trafficking to solid tumors, and an unfavorable tumor microenvironment. One approach to improve outcomes involves engineering bispecific CARs to targeting multiple antigens and thus surmount the heterogeneous target antigen expression on tumors. Other parallel strategies involve simultaneously targeting tumor antigens and suppressive mechanisms within the TME to enable T cell entry and create a receptive environment that maintains functional T cells. The talk will highlight Kalthera’s recent successes using bispecific CAR T therapies and future approaches making their way to the clinic.

We will introduce a novel class of high-sensitivity, inline mid-IR liquid analyzers. Based on ultra-high-brightness tunable quantum cascade lasers (QCL), these analyzers are enabling real-time biophysical characterization.

Purpose-fit designed bispecific DART® molecules are being developed for simultaneous blockade of PD-1 and LAG-3 (tebotelimab) or PD-1 and CTLA-4 (MGD019). Non-clinical biological characterization and preliminary findings from first-in-human clinical studies with these PD-1 based bispecific antibody molecules will be presented.

Bispecific antibodies can bridge T cells with tumor cells in a trans configuration, or engage two T cell targets in a cis configuration. We will discuss multiple applications of selectivity tuning for both configurations, including targeted costimulation and targeted de-repression.

Multi-specific antibodies have the unique ability to elicit an immune response at the site of a tumor. By minimizing the toxicities associated with a systemic immune response, tumor-targeted, immune agonist antibodies can increase the therapeutic index for new immune-activating cancer therapies. Using a unique sequence-based discovery approach, along with humanized transgenic rats, we have created a large collection of fully human antibodies targeting a variety of tumor antigens and activating receptors on immune cells.  Our novel discovery platform combines antibody repertoire deep sequencing, high-throughput gene assembly, and recombinant expression. Our lead program, TNB383B (BCMAxCD3), is currently in phase 1 clinical studies. In summary, we have created multiple platforms for tunable immune activation at the site of the tumor that work with a variety of tumor antigens.

NM21-1480 is a multispecific, antibody fragment-based cancer therapeutic in phase 1 clinical testing. NM21-1480 potently stimulates anti-cancer immune responses through concomitant induction of 4-1BB-signaling and PD-L1 blockade in the tumor microenvironment. Careful selection of format, epitopes, and affinities resulted in optimized activity and a favorable safety profile in non-human primates. Additional therapeutic approaches based on Numab’s MATCH^TM platform are presented.  

Recent work has demonstrated the promise of targeting receptor trafficking as a new mechanism for antibody therapy. In particular, multispecific antibodies that target a single transmembrane protein at multiple epitopes, so called "multi-epitopic" antibodies, achieve robust surface downregulation of growth factor receptor proteins. This presentation will explore the generality of multi-epitopic, antibody-mediated downregulation across receptor classes, and further elucidate the molecular pathways that enable manipulation of protein trafficking dynamics.

The extraordinary specificity of antibodies has led to their use in a wide variety of cancer treatments, including antibody-drug conjugates, bispecific constructs, and chimeric antigen receptor (CAR) T-cells.  Unfortunately, although antibodies have high specificity for their targets, the targets are not restricted to cancer, and expression of the targets in healthy tissue leads to on-target, off-cancer toxicity.  Link Immunotherapeutics has been developing novel pairs of synergistic bispecific antibodies to target the co-expression of two tumor antigens, allowing for a higher level of cancer specificity, as well as providing co-stimulation to the T cells leading to a more biologically relevant and robust activation of T cells than standard single bispecific antibodies. We hope that this dual bispecific strategy will lead to greater efficacy with reduced toxicity.

Alligator has developed Neo-X’, a concept aiming at enabling antigen presenting cells to efficiently enhance priming of neoantigen-specific T cells. Bispecific antibodies targeting CD40 and tumor antigens have been built using Alligators RUBY ™ format. The concept provides distinct advantages compared to cancer vaccines. In vivo and in vitro data, generated in a hCD40tg mouse model, supporting the concept will be presented.

This talk will cover the rationale for 4-1BB agonism; design and engineering of a tumor localized 4-1BB/HER2 agonist PRS-343; preclinical proof-of-concept and biomarker selection; and impact of translational studies on clinical testing.

Chimeric antigen receptors (CARs) are synthetic receptors that direct T cell activity toward diseased cells that they could not ordinarily recognize. Recent successes with this promising class of cell-based therapy have invigorated the immunotherapy field, but challenges still remain. This talk will discuss the role of engineered natural molecules in meeting these challenges. The IL13 ligand has been previously incorporated as the antigen recognition domain for CARs targeting IL13Ra2. This CAR architecture has demonstrated safety and success when engineered T cells were locally delivered in glioblastoma in early stage clinical trials. IL13Ra2 is an attractive target for a variety of other systemic malignancies as well. However, the interaction of IL13 with its other natural binding partner, IL13Ra1, which has ubiquitous low-level expression in normal tissue, raises concerns for systemic application of this CAR including 1) potential impedance of CAR T cell trafficking, 2) early exhaustion of CAR T cells due to encountering antigen en route to the tumor, and 3) on-target off-tumor toxicity. We have investigated the incorporation of engineered IL13 mutants (termed muteins) with enhanced selectivity for IL13Ra2 relative to IL13Ra1 as CAR antigen recognition domains. In vitro and in vivo selectivity experiments and T cell trafficking studies highlight the importance of drastically diminishing monovalent binding affinity to IL13Ra1 to enhance selectivity under extremely challenging antigen overexpression conditions. The engineering of other natural molecules to reshape the tumor microenvironment as CAR T cell “companions” will also be discussed.

Deep sequencing, high-throughput selection, and machine learning come together to guide protein engineering campaigns toward novel therapeutic and diagnostic tools.