CTLA-4 based Bispecific ADC Development Service

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.

Background

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.

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.

Our Service

CTLA-4-based Bispecific ADCs Services

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.

Highlights

• Precision Targeting Strategy: Creative Biolabs develops CTLA-4-based bispecific ADCs that precisely target and deliver cytotoxic agents to tumors, reducing systemic toxicity and enhancing treatment efficacy.
• Innovative Dual Antigen Engagement: Our CTLA-4 bispecific ADCs are uniquely designed to simultaneously target CTLA-4 and a second tumor-specific antigen, ensuring potent anti-tumor activity.
• Advanced ADC Development Platforms: Leveraging cutting-edge technology, Creative Biolabs provides streamlined and cost-effective ADC development services, optimizing project timelines.
• Tailored Therapeutic Development: We offer comprehensive services, from initial antibody production to final ADC characterization, custom-designed to meet diverse clinical and research needs.
• Diverse CTLA-4 Combinations for Enhanced Efficacy: Our team expertly constructs CTLA-4-based bispecific ADCs with multiple epitope pairings, including PD-L1 and OX40, to maximize therapeutic potential and reduce adverse effects.

FAQ

1. Q: How does CTLA-4 function in the development of bispecific ADCs?

   A: CTLA-4, a key immunoregulatory protein, is utilized in bispecific ADCs to target immune checkpoint pathways, enhancing tumor-specific immune responses while minimizing systemic toxicity.

2. Q: What makes CTLA-4 a significant target in bispecific ADC development?

   A: CTLA-4's role in downregulating T-cell activity makes it a strategic target for ADCs, aiming to modulate the immune environment within tumors and increase the efficacy of cancer treatments.

3. Q: How does Creative Biolabs ensure the effectiveness of CTLA-4-based bispecific ADCs?

   A: Through rigorous antibody development and optimization platforms, Creative Biolabs enhances the targeting accuracy and therapeutic index of CTLA-4-based bispecific ADCs.

4. Q: What specific CTLA-4-based bispecific ADC combinations does Creative Biolabs offer?

   A: Creative Biolabs has developed a variety of CTLA-4-based bispecific ADCs, including combinations with PD-1, PD-L1, EGFR, OX40, HER2, and GITR, to address different therapeutic needs and tumor profiles.

5. Q: How does Creative Biolabs optimize the CTLA-4-based bispecific ADCs for targeted delivery?

   A: Creative Biolabs utilizes advanced engineering techniques to optimize CTLA-4-based bispecific ADCs, ensuring precise conjugation and stability, which enhances the targeted delivery capabilities to tumor-specific antigens, maximizing therapeutic potential without systemic exposure.

Published Data

In this experiment, the CTLA-4 antibody-drug conjugate (ADC), Ipi-DM1, was designed to target and impair regulatory T cells (Tregs) by depleting them, leading to an unexpected depletion of B cells. CTLA-4 is primarily expressed on Tregs, and the Ipi-DM1 ADC selectively reduced Treg populations in a mouse model. This depletion led to a hyper-proliferation of both CD4 and CD8 T cells, which then caused autologous destruction of B cells. Notably, the B cell loss occurred in mature B cells rather than progenitor B cells, indicating that the mechanism of action primarily affected mature B cell populations. The experiment revealed a novel antagonistic relationship between T cells and B cells, with B cell depletion mediated through T cell activation. This process was partially rescued by anti-TNF-alpha, further confirming the role of T-cell-mediated destruction.

Fig.2 CTLA-4 antibody-drug conjugate enhances apoptosis in mature B cells within the bone marrow.¹

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Anti-CTLA4 ADC