LAGUNA BIO

This guide highlights the scientific background behind Laguna's therapeutic approach. Each statement links to a publication that you can access and download. If you only have time for a few papers, we think you’ll find these first few especially helpful. For additional information, please continue on.

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• Laguna Listeria cannot grow extracellularly, which solves safety concerns from previous trials using LADD

• Listeria’s effect on the immune system can be harnessed for immunotherapy

• γδ T cells are exceptionally promising for immunotherapy

• Listeria potently activates γδ T cells

• LADD-based strains, which serve as the foundation of Laguna Listeria, profoundly activated and expanded γ9δ2 T cells in humans (CONFIDENTIAL, unpublished)

• Bispecific T cell engagers (BiTEs) direct γδ T cells against tumors

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Listeria

History and safety

Listeria has a long history in the clinic

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LADD is the foundational strain for Laguna Listeria

• Listeria-based therapeutics were generally well-tolerated in the clinic, but significant adverse events associated with extracellular growth were observed

• In clinical trials using LADD, there was one case of listeriosis

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Laguna Listeria cannot grow extracellularly, which solves safety concerns from previous trials using LADD
 

Activation and expansion of γδ T cells

γδ T cells are exceptionally promising for immunotherapy

• γδ T cell tumor infiltration is correlated with favorable outcomes, including in solid tumors

• γδ T cells can cross-present to ɑβ/CD8 T cells leading to robust and durable anti-tumor activity

• γδ T cells can be difficult to study in mice

• γδ T cell cytotoxicity is best characterized by their transcriptional profile

 

γδ T cells are activated and expanded through pathogen-associated molecular pattern molecules (PAMPs) and damage-associated molecular patterns (DAMPs)

• PAMPs and DAMPs are the necessary “signal 0” for an effective immune response

• γδ T cells respond directly to PAMPs

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In humans, γδ T cells have evolved to be exquisitely sensitive to Listeria

• Listeria’s effect on the immune system can be harnessed for immunotherapy

• Listeria is a potent activator of PAMP and DAMP signaling

• Listeria potently activates γδ T cells

• LADD-based strains, which serve as the foundation of Laguna Listeria, profoundly activated and expanded γ9δ2 T cells in humans (CONFIDENTIAL, unpublished)

• Listeria activates and expands γδ T cells through mechanisms other than HMBPP, likely PAMPs and DAMPs - No existing small molecule or antibody-based activation of γδ T cells can stimulate multiple paths of activation like Listeria

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Other approaches are poor γ9δ2 T cell activators

• Dead Listeria are poor immune activators, necessitating live attenuated strains

• Phosphoantigens (e.g., HMBPP) alone struggle to activate and expand γδ T cells

• Repeated phosphoantigen administration can impair γδ T cells - However, repeated administration of Listeria leads to continuous activation and expansion of γδ T cells in our results from a human study

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Other immune cell populations have limitations for immunotherapy

• NK cells have struggled in solid tumor treatments

• CD8 cell effectiveness decreases with chronic antigen exposure

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Potential with other immune cells

MAIT cells are another promising immune population for immunotherapy

• MAIT cells respond to ligand 5-OP-RU

• Listeria can express 5-OP-RU, and profoundly activate and expand MAIT cells (CONFIDENTIAL, unpublished)

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Biologics: mAbs and bispecifics / BiTEs

Several companies are developing γ9δ2-engaging bispecifics

• ImCheck showed safety in clinical trial

• Shattuck showed efficacy in in vitro studies

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Cytokine release syndrome (CRS) is a concern with biologics, but can be managed through several strategies

• Step-fractionated dosing mitigates peak cytokine levels without compromising tumor response (mosunetuzumab, Blincyto)

• Affinity tuning can decrease off-target effects

• Increasing the number of tumor binding sites can increase the therapeutic index

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Graft versus host disease (GvHD) is a concern with traditional ɑβ CAR-T therapy, but is not a concern with γδ T cells

• CAR-T therapy dosing of ~10^8 balances safety and efficacy considerations

• Traditional CAR-T is limited by GvHD, but γδ T cells don’t cause GvHD

• LADD expansion of γ9δ2 T cells achieves at least 10^9 γδ T cells in the peripheral blood, which is 10x more than GvHD-limited CAR-T dosing

 

Activation + biologics combination therapy

Pre-clinical models show the potential of pairing activated γ9δ2 T cells and MAIT cells with biologics:

• Allogeneic γ9δ2 T cells expanded ex vivo with IL2 and BrHPP, then paired with monoclonal antibodies (e.g., Herceptin)

• Allogeneic γ9δ2 T cells expanded ex vivo with IL2 and zoledronate, then paired with CD3 bispecific (e.g., Blincyto)

• Allogeneic γ9δ2 T cells expanded ex vivo with IL2 and IL15 and zoledronate, then paired with γ9δ2-engaging bispecific

• MAIT cells expanded ex vivo with IL2 and IL15, then paired with MAIT-engaging bispecific

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Activation as a monotherapy

γδ T cells that are activated and expanded by Listeria can improve outcomes for people with heme malignancies after receiving hematopoietic stem cell therapy (HSCT):

• Activating and expanding γδ T cells helps prevent infection and kill cancer cells in patients receiving ɑβ/CD8 T cell-depleted HSCT

• For pediatric patients receiving T cell-depleted haplo-HSCT in combination with zoledronate to activate endogenous γδ T cells:

  • γδ T cell differentiation and cytotoxicity improves the outcome of pediatric patients receiving ɑβ/CD8 T cell-depleted HSCT

  • Repeated dosing of zoledronic acid resulted in greater activation and expansion of γδ T cells leading to fewer GvHD and lower transplant-related deaths

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