Development of 4-1BB-based Bispecific ADCs

Bispecific antibody-drug conjugates (ADCs) have obtained a lot of attention due to its great potential in cancer treatment, which possesses significant advantages including the specificity of the targeted antibody and potent antitumor activity of small molecular drug. Based on the well-established ADC and bispecific antibody (bsAb) development platforms, Creative Biolabs offers customized bispecific ADCs development services to achieve your goals.

The Overview of 4-1BB

As a tumor necrosis factor receptor (TNFR) superfamily (TNFRSF) member, 4-1BB contains four cysteine rich domains (CRD) in the N-terminal extracellular region connected to a C-terminal cytoplasmic region that contains a TNF receptor-associated factor (TRAF) binding motif to initiate subsequent signaling. 4-1BB acts as a costimulatory molecule on activated T cells to enhance their response to antigen and can also aid the activation of other cells such as NK cells. The ligand of h4-1BB, h4-1BBL, is a member of the TNF ligand superfamily expressed on activated antigen-presenting cells. On T cells and NK cells, 4-1BB signaling can inhibit apoptosis while augmenting proliferation and effector functions such as cytokine production or CTL activity that can lead to the eradication of established tumors. The antitumor properties have made 4-1BB a uniquely appealing target for cancer immunotherapy.

Based on sequence variance and structural organization, TNF family ligands have been divided into conventional, EF disulfide, and divergent families. The conventional family members (such as TNF, RANKL, CD40L) share sequence identity and exist as trimers with a bell-shaped architecture. The members of the EF-disulfide group (such as APRIL and TWEAK) contain disulfide bonds between the E and F strands resulting in a more globular shape and bind very small atypical TNFRs (BCMA, TACI, Fn14). The third group contains TNF ligands (such as OX40L, GITRL, 4-1BBL, CD30L) that exhibit greater sequence divergence and have a comparably shorter TNF homology domain (THD).

Fig.1 Structure of h4-1BB ligand in the h4-1BB/4-1BBL complex. (Bitra, 2018)

Antibodies-based Therapeutics Targeting 4-1BB

The initial evidence that anti-4-1BB mAbs may have strong antitumor effects emerged from studies on the highly tumorigenic P815 mastocytoma and poorly immunogenic Ag104A sarcoma. Administration of anti-4-1BB mAb eradicated established tumors in both models and generated increased numbers of tumor-specific cytotoxic T cells. The two anti-4-1BB mAbs currently in the clinic are urelumab (BMS-663513), a fully humanized IgG4 mAb, and utomilumab (PF-05082566), a fully human IgG2 mAb. Urelumab is now being tested in combination with other therapeutic agents in multiple clinical trials for the treatment of colorectal cancer, relapsed or refractory B-cell non-hodgkin lymphoma, and multiple myeloma. PF-05082566 is currently in three clinical trials. The results of the phase I monotherapy study indicated that PF-05082566 did not induce any dose-limiting toxicities.

What Can We Do for You?

Multiple 4-1BB-targeted bsAbs are in preclinical development and have demonstrated promising early data. The bsAbs are designed to promote target-mediated clustering of 4-1BB, in the absence of the tumor target, minimal clustering will occur and immune activation will be limited. In the tumor microenvironment, the bsAb functions as a bridge between cells expressing HER2 or fibroblast activation protein and activated immune cells that express 4-1BB. By locking immune effectors and target cells near, the bsAb theoretically enhances 4-1BB clustering and signal induction. For example, the HER2 x 4-1BB bispecific molecule PRS-343 is designed to activate 4-1BB in a localized manner to provide a safer alternate therapeutic strategy to patients in a broad range of HER2-positive malignancies.

With extensive experience and advanced platform, Creative Biolabs provides customized bispecific ADCs development services. We have constructed different epitope combinations for 4-1BB-based bispecific ADCs development, including 4-1BB x PD-L1, 4-1BB x FAP, 4-1BB x EGFR, 4-1BB x 5T4, 4-1BB x GPC3, 4-1BB x HER2, and 4-1BB x PSMA. Please feel free to contact us for more details and our scientists will tailor the most reasonable scheme for your projects.

Reference

1. Bitra A.; et al. Crystal structures of the human 4-1BB receptor bound to its ligand 4-1BBL reveal covalent receptor dimerization as a potential signaling amplifier. Journal of Biological Chemistry, 2018.

For Research Use Only. NOT FOR CLINICAL USE.