Harnessing the immune system through T cell engagers (TCE) has the potential to revolutionize cancer treatment. However, off-tumor toxicities of first-generation TCEs have limited their therapeutic potential. Revitope’s lead candidate, REV403, is the TwoGATE, a split anti-CD3 paratope enabling true dual Ag “AND” gate targeting the inactive prodrug components to EGFR and PDL1 on the same tumor cell where they are activated resulting in tumor-specific restoration of the CD3 binding complex. Preclinical data including NHP tolerability of REV403 and our thoughts on ways to overcome the barriers to successful T cell redirection in solid tumors will be discussed.

PB203 stands alone as the sole Fc fusion protein in the world that simultaneously engages PD-L1, VEGF-A, and PlGF. PB203 has demonstrated synergy with chemotherapy in the treatment of pancreatic cancer by altering the tumor microenvironment. Through structural fine-tuning, our team has enhanced its stability and functionality. Exhibiting superior in vivo performance, this multi-specific protein drug is being developed as a viable and promising treatment for cancer patients.

• What are the challenges and opportunities in targeting co-stimulators for IO
• What are the challenges and opportunities in targeting cytokines for IO 
• How can we build conditional-active agonistic co-stimulators and cytokines to target only right type of cells in the right place?

• How to normalize tumor blood vessels for better drug delivery into solid tumor?
• How to modulate TME to optimize immune cell’s anti-tumor activity?
• How to reduce hypoxia in solid tumor TME?
• Bispecific Ab ADC better than mAb ADC ?​

Anti-CD3-based bispecific T cell engagers (BiTE) showed limited clinical efficacy in solid tumors and caused significant cytokine storm. Signal regulatory protein-a (SIRPa) is a major myeloid cell inhibitory receptor that engages the “don’t eat me” signal from CD47 expressed on tumors and normal tissues. Similar to BITE where T cells are activated by the CD3 antibody, we constructed a novel bispecific macrophage engager (BiME) platform where macrophage is activated by a SIRPa inhibitory antibody that is directed to a particular tumor via the targeting of the tumor-associated antigen (TAA) antibody, resulting in phagocytosis of the tumor. 

T cells recognize intracellular targets presented by HLA to enable potent anti-tumor immune responses, and these targets can be leveraged to generate off-the-shelf therapeutics using T cell bispecific engagers to treat a broad patient population. We've developed 3T-TRACE to rapidly identify the antigens of orphan T cells from patient tumors and a TCR mimetic platform to rapidly generate potent and specific binders for therapeutic development.

T cell bispecific antibodies have been effective in hematologic malignancies, but have shown limited efficacy in solid tumors. One of the critical factors behind the limited efficacy of T cell bispecifics is the suppressive tumor microenvironment. To overcome this, we developed a novel T cell bispecific antibody which uses a unique mechanism to remodel the tumor microenvironment and improve T cell activation status. The preclinical data will be presented.

Alligator´s Neo-X-Prime platform consists of bispecific antibodies targeting CD40 and tumor-associated antigens (TAA) that efficiently enhance cross priming of tumor-specific T cells. Neo-X-Prime bispecific antibodies display superior preclinical anti-tumor efficacy compared to the combination of the two monospecific antibodies. We have demonstrated that the lead Neo-X-Prime candidate drug – ATOR-4066, targeting CD40 and CEA – is safe and induces potent anti-tumor effects in preclinical models.

We developed a method that can site-specifically and covalently attach an anti-CD3 scFv or anti-CD3 nanobody to any off-the-shelf, human IgG, or patient’s own anti-tumor antibodies. Biggest advantage of this system is that it does not require antibody engineering, cloning, or any modifications. As a result, we can rapidly prepare bispecific antibodies with high purity and are able to combine it with personalized tumor targeting autoantibody-based T cell immunotherapy. 

Cancer immunotherapies have revolutionized cancer treatment. However, the majority of patients either do not respond or relapse soon after treatment with checkpoint inhibitor(s). In this talk, we will share our strategy and progress in developing innovative conditionally active bi-/multi-specific cytokines or co-stimulators that have significant therapeutic window. They become very active precisely on tumor reactive T cells only in the tumor microenvironment, but are extremely weak in the peripheral blood.

T cell engagers (TCEs) are realising their promise with several recent approvals and multiple ongoing clinical trials. Their efficacious mechanism of action does come with a cost, as grade =3 adverse events are commonplace. NovalGen’s autoregulation technology has the potential to reduce these life-threatening toxicities and extend the TCE therapeutic window, enhancing patient safety. NVG-222 is a next-generation ROR1-targeting autoregulating TCE primed for entry into the clinic in 2024Q1.

Bispecific antibodies (bsAbs) have been developed to enhance tumor targeting while reducing systemic toxicity. However, it is still unclear how to design bsAb to maximize its therapeutic index (TI). I will describe computational models that predict PK, efficacy, toxicity, and TI of bsAbs. I will demonstrate that our in silico predictions match with in vivo observation, and these models can be used to guide the rationale design of bsAbs.

First-generation bispecific conditional-agonists were designed for maximum potency. Major challenges of such an approach include toxicity, immune exhaustion, lack of memory, and response durability. We developed a bispecific platform that can simultaneously adjust synaptic distance and apparent affinity to optimize signal strength. This system allows for rapid identification of conditional agonists that induce a range of properties. As such, we are able to generate conditional agonists that can function at low effector cell to tumor densities and maintain immune fitness and tune such proteins for little to no cytokine release for inclusion of a tumor-targeted controlled pro-inflammatory payload.