Tallac Therapeutics focuses on novel therapeutics engaging both innate and adaptive anti-tumor immunity. We developed a novel Toll-like Receptor Agonist Antibody Conjugate (TRAAC) platform to deliver a potent TLR9 agonist (T-CpG) for targeted immune activation via systemic administration. TRAAC molecules targeting either immune cell receptors or tumor-specific antigens demonstrated robust immune modulation and potent single-agent anti-tumor activity in preclinical settings, suggesting therapeutic potential across multiple solid tumor malignancies.

Gastric inhibitory polypeptide receptor (GIPR) plays a role in regulation of body weight and GLP-1 receptor agonists are known to control blood glucose levels. We will present the discovery of a novel GIPR antagonistic antibody and GLP-1 peptide conjugate (AMG 133) that demonstrated robust body weight reduction and significant improvement of metabolic parameters in preclinical models. AMG133 also displayed efficacy and tolerability in the Phase I clinical trial.

Bispecific T cell engager (BiTE)-based cancer immunotherapies that activate the cytotoxic T cells of a patient’s own immune system have gained momentum with the recent FDA approval of Blinatumomab for treating B cell malignancies. However, this approach has had limited success in targeting solid tumors. We have developed of BiTE-sialidase fusion proteins that enhance tumor cell susceptibility to BiTE-mediated cytolysis by T cells via selective desialylation at the T cell-tumor cell interface that results in better immunological synapse formation. We demonstrated that BiTE-sialidase fusion proteins exhibit remarkably increased efficacy as compared to BiTEs alone both in vitro and in an in vivo xenograft solid tumor model. We believe that BiTE-sialidase fusion proteins have great potential as candidates for the development of next-generation bispecific T cell engaging molecules for cancer immunotherapy.

T cells require multiple signals (TCR engagement, costimulation, cytokines) for optimal activation, survival, and differentiation. However, T cells and positive signals are found sparingly in solid tumors. Traditional bispecific T cell engagers provide only TCR engagement (CD3) and may drive an incomplete anti-tumor response. We engineered CD28 bispecific antibodies and cytokine mimetics capable of providing T cells with additional signals and show that they provide enhanced activity over traditional bispecifics.

The DutaFab platform delivers fully human bispecific Fab molecules, which are structurally indistinguishable from a conventional monospecific Fab and can be reformatted into diverse antibody formats as required. Heavy and light chains both contribute to each of the two adjacent paratopes, which can be maturated independently to high affinities and combined in a modular way. Unique MoAs are achievable by either simultaneous or mutual exclusive binding to the two targets.

Harnessing the immune system has revolutionized cancer treatment. However, on-target off-tumor toxicities limit their therapeutic potential. Revitope is developing a new class of cancer therapeutics engineered with a split anti-CD3 paratope that enables targeting each inactive half-paratope to a different antigen on the same tumor cell. TwoGATE have pM potency in vitro, potently regress tumors in vivo, are well-tolerated in non-human primates, and have highly favorable developability properties.

Immunotherapies directed at MHC-I complexes have enabled the direct targeting of intracellular oncoproteins at the cell surface. We asked whether covalent drugs that alkylate mutant oncoproteins could act as haptens to generate MHC-I-restricted neoantigens. Here we report that KRAS G12C mutant cells treated with the covalent inhibitor ARS1620 present ARS1620-modified peptides in MHC-I complexes. Using ARS1620-specific antibodies, we show that these haptenated MHC-I complexes can serve as tumor-specific neoantigens and that a bispecific T cell engager construct based on a hapten-specific antibody elicits a cytotoxic T cell response against KRAS G12C cells, including those resistant to direct KRAS G12C inhibition.

Poor brain delivery is a major hurdle in the development of biological therapeutics for neurologic diseases because of poor Blood-Brain Barrier (BBB) penetration. Numerous BBB shuttles based on single domain VNAR antibodies were developed by Ossianix. These include TXP1 which was demonstrated to penetrate the brain with high efficiency when inject at a low therapeutic dose in non-human primates with an over 30-fold increase in comparison to the control.

Developing VHH for medical use involves many engineering steps after camelid immunization to humanize, affinity mature, remove liabilities, and engineer Protein A binding. Improving one characteristic often impairs another. We devised a new library that enables bypassing many of these processes: human liability-free CDR1-2 are inserted into clinical VHH scaffolds (humanized) and filtered for Protein A binding. These are combined with >108 CDR3 and are able to yield VHH with drug-like characteristics.

Rapid, cost-effective, and widely available diagnostics are needed to monitor and mitigate the spread of SARS-CoV-2 and future outbreaks. An engineered antibody-enzyme fusion protein recognizes SARS-CoV-2-specific patient antibodies and catalyzes the conversion of sucrose to glucose, allowing quantification of antibodies against disease antigens using commercial glucometers. Engineering of the detection antibody, as well as a substation of the capture antigen, are expanding the applications and efficacy of this diagnostic.

Developing peptide binders against intracellular proteins and protein-protein interfaces remains a challenge with current methods and scaffolds. We recently developed computational methods to design peptides with enhanced membrane permeability and oral bioavailability. We are further integrating our computational methods with high-throughput peptide synthesis to design peptide binders for antibiotic, antiviral, and other therapeutic applications. Overall, these methods present avenues for binding intracellular targets currently considered "undruggable" or "difficult to drug."

We evaluated affibody-based concepts for bivalent and bispecific targeting of HER3 and EGFR. For HER3 in mice, we demonstrated efficient tumor growth inhibition. For EGFR, we developed an affibody-based prodrug concept with conditional targeting conferred by an anti-idiotypic affibody masking domain, and activation by cancer-associated proteases, to achieve impressive selective tumor-targeting in tumor-bearing mice. Will be further present how cytotoxic compounds conjugated to the affibody constructs improve their therapeutic efficacy.