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TATX-24: CD3δε Fabs

Many solid tumors are poorly immunogenic as the binding of monoclonal antibodies to the tumor associated antigen (TAA) often fails to induce the required immune response for tumor cell killing. This renders immunotherapy less effective. Combining anti-TAA binding capability with anti-CD3 T cell engagement into one bispecific molecule enables the recruitment and activation of T cells to increase immunotherapy efficacy. The first generation of T cell engagers available on the market have a high affinity for CD3 and induce potent tumor cell killing, but also cause the release of high levels of cytokines, leading to severe side effects and a narrow therapeutic window. Talem has developed anti-CD3 Fabs specifically directed against CD3δε, which are expected to reduce cytokine release. These Fabs are available to combine with anti-TAA arms of potential partners for the generation of novel T cell engaging bi-, tri- and multi- specific molecules.

Format: CD3δε targeting fragment antigen-binding (Fab) arm for a bi- or multi-specific

Stage: Lead candidate

Mode of action: T cell engagement

Focused indication: Bi-, tri- and multi-specifics

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TATX-26:TIM3

T-cell immunoglobulin and mucin-domain containing-3 (TIM3) is an immune checkpoint protein that plays a key role in regulating immune responses. Its expression is limited to immune cells. In healthy tissues, TIM3 plays a nuanced role in regulating immune responses and maintaining immune homeostasis. When expressed on tumor infiltrating leukocytes, TIM3 acts as a negative regulator of immune activation by promoting T-cell exhaustion, limiting immune responses against tumor cells, and facilitating an immunosuppressive environment that supports tumor growth. Its interaction with ligands impairs the ability of T-cells to attack tumor cells. Consequently, TIM3 has emerged as a potential target for cancer immunotherapy. Targeting strategy undisclosed.

Format: Undisclosed

Stage: Lead selection

Mode of Action: Undisclosed

Indication: Solid tumors

Technologies: Wet lab and AI

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TATX-27: CD38

CD38 is a cell surface enzyme involved in regulating intracellular calcium levels and plays a key role in the immune response, cellular signalling, and metabolism under normal conditions. Moreover, CD38 is involved in cell adhesion and communication, particularly in immune cells like T-cells and B-cells, aiding in their interaction and response to pathogens. In cancer, CD38 expression is often upregulated as a resistance mechanism following PD1/PD-L1 blockade in both tumor cells and leukocytes. CD38 can facilitate the creation of an immunosuppressive environment by inhibiting immune cell activity, including T-cells and natural killer cells, allowing tumors to evade immune surveillance. Targeting strategy undisclosed.

Format: Undisclosed

Stage: Lead selection

Mode of Action: Undisclosed

Indication: Haematological malignancies

Technologies: Wet lab and AI

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TATX-28: B7H3

Under normal conditions, B7-H3 (also known as CD276), a member of the B7 family of immune checkpoint molecules, plays an essential role in regulating immune responses. B7-H3 can suppress T-cell proliferation and cytokine production, helping to maintain immune homeostasis and prevent excessive immune responses. In many cancers, tumor cells express high levels of B7-H3, which can inhibit anti-tumor immune responses. Additionally, B7-H3 is expressed on tumor infiltrating leukocytes, where it can dampen immune function and create an immunosuppressive microenvironment. Its unique expression profile in cancer and immune modulating role makes B7-H3 a target of interest for cancer immunotherapy. Targeting strategy undisclosed.

Format: Undisclosed

Stage: Lead selection

Mode of Action: Undisclosed

Indication: Solid tumors

Technologies: Wet lab and AI

Partner:

TATX-112: TrkB

Tropomyosin receptor kinase B (TrkB) is a receptor tyrosine kinase (TK) that is implicated in various solid tumors. Ordinarily, TrkB expression is confined to the central nervous system where it is important for maintaining normal brain function. Aberrant and overexpression of TrkB is implicated in various solid malignancies and associated with poor prognosis. Currently, therapeutic options for TrkB targeting are restricted to pan-Trk inhibitors, which lack specificity and cause side effects. The use of monoclonal antibodies specifically binding TrkB for the intracellular delivery of toxic payloads (i.e. ADC) is anticipated to increase safety and efficacy of TrkB-directed cancer therapies. Additionally, large molecules, such as antibodies, do not readily cross the blood-brain-barrier, further reducing the risk of on-target side effects. Highly specific anti-TrkB internalizing antibodies are being developed to combine with ADC platform technologies of potential partners.

Format: Monoclonal antibody for ADC-based therapeutics

Stage: Lead selection

Mode of action: Internalization for delivery of toxic payload into tumor cells

Indication: Solid tumors

Technologies: Wet Lab and  AI

Partner:

TATX-200: TrkBxCD3 Bispecific Antibodies

Breast cancer (BC) accounts for 30% of all new female cancer cases each year. While there are good treatment options available, there are still hard to treat or unresponsive subtypes of BC, such as triple negative BC (TNBC). The (over)expression of the Tropomyosin kinase B (TrkB) and (over)activation of the TrkB signaling pathway play an important role in various solid malignancies, including BC, and are associated with poor prognosis. Preclinical studies have demonstrated that targeting the TrkB pathway can reduce BC cell growth and metastasis, but current TrkB-directed treatment options are not specific. Additionally, breast tumors are not highly immunogenic, rendering immunotherapy less effective. By combining Talem’s proprietary anti-TrkB antibody arms with proprietary anti-CD3δε T cell engaging antibody arms in a bispecific format, a novel and effective immunotherapeutic molecule against BC is being developed with the aim of improving therapeutic options.

Format: Bispecific antibody, T cell engager

Stage: Lead candidate

Mode of action: T cell engagement

Indication: Breast cancer (TNBC, HER2 neg.) and other solid tumors

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TATX-21: ALK1

Activin receptor-like kinase 1 (ALK1), a member of the TGF-β receptor superfamily, is preferentially expressed on endothelial cells. Its ligands are BMP9 and BMP10. Impaired BMP9/ALK1 signaling is associated with various vascular pathologies such as diabetic retinopathy, diabetic kidney problems and pulmonary arterial hypertension (PAH); all chronic and hard to treat conditions. Enhancing signaling via the BMP9/ALK1 pathway has been demonstrated to reduce symptoms associated with PAH and to prevent hyperglycemia-induced vascular permeability in preclinical animal models. Enhancing ALK1-signaling by treatment with BMP9 carries the risk of side effects through interaction with its other cognate receptors. Therefore, Talem is developing agonist antibodies specific for ALK1 with the aim to generate a safe and effective therapeutic for these vascular pathologies.

Format: Monoclonal antibody

Stage: Lead Candidate Selection

Mode of action: Stimulation of signaling (agonist)

Indications: Diabetic retinopathy and pulmonary arterial hypertension