Development of CTLA-4-based Bispecific ADCs

Bispecific antibody-drug conjugate (ADC) is a type of novel anticancer agent developed to selectively deliver a cytotoxic drug to tumors while minimizing systemic toxicity to healthy tissues. The bispecific antibody is one of the critical components of the bispecific ADC construction, which can specifically target two different tumor-antigens. With abundant experience in antibody production and ADCs development, Creative Biolabs provides a full range of bispecific ADCs development services. Our ADC platforms are optimized to help you promote your projects in a time and cost-effective manner.

The Overview of CTLA-4

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), also known as CD152, was initially described during a search for cytotoxic genes using subtractive hybridization. It is a type 1 transmembrane glycoprotein of the immunoglobin superfamily, 223 amino acids (aa) in length, with a 35 aa signal peptide, and it is found as a covalent homodimer of 41-43 kDa. The extracellular architecture of CTLA-4 is characterized by a single IgV-like domain containing a ligand-binding site. Its ligands are CD80 (B7-1) and CD86 (B7-2), found on antigen-presenting cells and T-regulatory (T-reg) cells, with binding causing downregulation of activated T cell activity and upregulation of suppressive T-reg function.

Homodimerization of CTLA-4 is mediated by cysteine-dependent bonding at position 122 in the stalk region and by N-glycosylation at positions 78 and 110. The cytoplasmic portion of CTLA-4 is 36 aa in length and lacks any intrinsic enzymatic activity. It contains a lysine-rich motif located proximal to the membrane, two tyrosine residues at positions 165 and 182, and a proline-rich region starting at position 169. Altogether, these areas have been implicated in the association of CTLA-4 with a variety of signaling molecules modulating its function. The simplicity of this structure disguises its critical function as a negative regulator of T cell-mediated immune responses.

Structure of human CTLA-4 dimer and sequence alignment of the CTLA-4 family. Fig.1 Structure of human CTLA-4 dimer and sequence alignment of the CTLA-4 family.

Antibodies-based Therapeutics Targeting CTLA-4

Ipilimumab, an anti-CTLA-4 antibody, was the first checkpoint inhibitors to be licensed in 2011 and was initially used for the treatment of metastatic melanoma. Ipilimumab is now indicated in multiple tumor types. It has a high surface area at its binding site and has a dissociation constant of 5.25 nM, with a large surface area buried at its binding surface with CTLA-4. Tremelimumab is another monoclonal antibody targeting CTLA-4 but has not yet been licensed for any indication, although it has orphan drug status for the treatment of mesothelioma. Tremelimumab is an IgG2 antibody, and this subtype is thought to have less complement activation and antibody-dependent cell-mediated cytotoxicity. It is currently in ongoing clinical trials, in particular in combination with durvalumab.

What Can We Do for You?

ATOR-1015 is a human CTLA-4 x OX40 targeting IgG1 bispecific antibody generated by linking an optimized version of the Ig-like V-type domain of human CD86, a natural CTLA-4 ligand, to an agonistic OX40 antibody. ATOR-1015 induces T-cell activation and Treg depletion in vitro. Treatment with ATOR-1015 reduces tumor growth and improves survival in several tumor models. By targeting CTLA-4 and OX40 simultaneously, ATOR-1015 is directed to the tumor area where it induces enhanced immune activation and thus has the potential to be a next-generation CTLA-4 targeting therapy with improved clinical efficacy and reduced toxicity. ATOR-1015 is also expected to act synergistically with anti-PD-1/PD-L1 therapy.

With over a decade of extensive experience in developing ADCs, Creative Biolabs is professional in supporting novel bispecific ADCs development projects. We have constructed different epitope combinations for CTLA-4-based bispecific ADCs development, including CTLA-4 x PD-1, CTLA-4 x PD-L1, CTLA-4 x EGFR, CTLA-4 x OX40, CTLA-4 x HER2, and CTLA-4 x GITR. Our scientists are proud to tailor and conduct the best-fit proposal for the generation of bispecific ADCs to meet your particular application requirements. If you are interested in our services, please contact us for more details.


For Research Use Only. NOT FOR CLINICAL USE.


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