PRLR based Bispecific ADC Development Service

As novel targeted therapy with great potential, bispecific antibody-drug conjugates (ADCs) targeting two different antigens inherit superiorities of the bispecific antibody with the drug module, and more remarkably, expand the therapeutic window. Creative Biolabs is a global leader in providing ADCs development services for both research and industrial institutions. Our world-class facilities are backed by a highly experienced scientist team to offer integrated services from antibody discovery, drug conjugation to ADCs characterization. We strive to offer tailored solutions for your bispecific ADCs development.

Background

The Overview of PRLR

The prolactin receptor (PRLR) and its primary ligand prolactin (PRL) constitute a complex receptor system, linked to more than 300 biological functions ranging from reproduction and cell differentiation to immune responses. It is best known for its role in mammary gland development and lactation as well as the pathology hyperprolactinemia, and it also involves in reproductive disorders as well as breast and prostate tumorigenesis, and has therefore attracted significant pharmaceutical interest.

The PRLR is believed to stand at the plasma membrane as a non-covalent homodimer. Ligand-induced activation of the PRLR involves the formation of an asymmetric trimer including one ligand and two receptor moieties. The formation of this complex involves three intermolecular interactions: PRL site 1 interacts with one PRLR moiety, PRL site 2 interacts with the second PRLR moiety, and the stem domains of the two PRLR extracellular domains interact with each other (site 3). As determined by surface plasmon resonance for the three PRLR natural ligands, site 1 has a high affinity (nanomolar range) while the combined affinities of sites 2 and 3 are in the micromolar range.

Fig.1 Structure of PRL/PRLR complex and binding sites for PRLR blockers.¹

Antibodies-based Therapeutics Targeting PRLR

Two different neutralizing monoclonal antibodies (mAb) have been reported by Novartis and Bayer. Both mAbs were shown to efficiently inhibit PRL-induced activity in in vitro and in vivo preclinical models. An important finding is that PRLR-signaling inhibition results in the upregulation of circulating PRL levels, as expected based on negative feedback regulation of pituitary PRL secretion. A clinical trial involving the administration of this mAb (LFA102) to patients presenting with advanced, PRLR-positive prostate cancer or breast cancer failed to provide any clinical benefit despite efficient inhibition of PRLR signaling as assessed by the dose-dependent escalation of PRL circulating levels.

In addition, an anti-PRLR antibody-drug conjugate (ADC), REGN2878-DM1, was developed for targeting PRLR-positive breast cancer. REGN2878-DM1 is comprised of a fully human high-affinity function-blocking anti-PRLR IgG1 antibody (REGN2878) conjugated via a noncleavable SMCC linker to the cytotoxic maytansine derivative DM1. Both unconjugated REGN2878 and conjugated REGN2878-DM1 block PRL-mediated activation in vitro and are rapidly internalized into lysosomes. In vivo, REGN2878-DM1 demonstrated significant antigen-specific antitumor activity against breast cancer xenograft models. These results illustrate promising antitumor activity against PRLR-positive breast cancer xenografts and support the evaluation of anti-PRLR ADCs as potential therapeutic agents in breast cancer.

Our Service

PRLR-based Bispecific ADCs Services

A HER2 x PRLR bispecific ADC has recently been developed. In contrast to HER2, it was found that PRLR is rapidly and constitutively internalized, and traffics efficiently to lysosomes. Non-covalently crosslinking HER2 to PRLR at the cell surface, using a bispecific antibody that binds to both receptors, dramatically enhances the degradation of HER2 as well as the cell-killing activity of a noncompeting HER2 ADC. Furthermore, in breast cancer cells that co-express HER2 and PRLR, the HER2 x PRLR bispecific ADC kills more effectively than HER2 ADC. These results emphasize that coupling an ADC target to a rapidly internalizing protein may be a useful approach to enhance the internalization and cell-killing activity of ADCs.

In terms of our advanced technology platforms, scientists at Creative Biolabs are confident in offering high-quality bispecific ADCs development services to assist your valuable projects. A series of bispecific ADCs candidates can be rapidly developed with desired specificity to meet your particular application requirements. Should you be interested in PRLR-based bispecific ADC development services, please contact us for more details.

Highlights

• Rapid Internalization for Enhanced Efficacy: PRLR is rapidly internalized and traffics to lysosomes, which improves the cell-killing activity of bispecific ADCs, making it a potent target for cancer therapy.
• Superior Antigen Targeting: By utilizing both HER2 and PRLR as targets, Creative Biolabs enhances the degradation of HER2 and significantly boosts the therapeutic activity of bispecific ADCs in breast cancer treatment.
• Experienced ADC Development Team: With a highly experienced scientific team, Creative Biolabs integrates antibody discovery, drug conjugation, and ADC characterization, ensuring efficient PRLR-based bispecific ADC development.
• Advanced Technology Platforms: Creative Biolabs leverages state-of-the-art technology to develop bispecific ADCs targeting PRLR, offering optimized therapeutic solutions for enhanced cancer treatment efficacy.
• Efficient Antibody-Drug Conjugation: Creative Biolabs applies cutting-edge conjugation strategies to ensure precise attachment of cytotoxic drugs to PRLR-targeting antibodies, improving therapeutic potency and reducing off-target effects.

FAQ

1. Q: What specific PRLR-based bispecific ADC combinations does Creative Biolabs offer?

   A: Creative Biolabs has developed a variety of PRLR-based bispecific ADCs, including combinations with HER2, to address different therapeutic needs and enhance the internalization and cell-killing activity of ADCs in tumor cells.

2. Q: How does PRLR function as a target in ADC therapies?

   A: PRLR is involved in numerous biological functions and pathologies, including cancer, making it a valuable target for ADC therapies due to its efficient internalization and subsequent therapeutic payload delivery.

3. Q: What makes PRLR an attractive target for bispecific ADCs?

   A: PRLR's rapid internalization and direct trafficking to lysosomes make it ideal for ADCs, ensuring effective delivery and activation of cytotoxic agents within cancer cells.

4. Q: Can Creative Biolabs develop ADCs targeting both PRLR and another antigen?

   A: Yes, Creative Biolabs can develop bispecific ADCs targeting PRLR and another antigen, enhancing receptor degradation and cell-killing activity, particularly in cancers expressing multiple relevant receptors.

5. Q: What are the key considerations in the design of PRLR-targeted ADCs?

   A: Key considerations include ensuring PRLR's high expression on target cells, understanding its internalization kinetics, and designing ADCs to optimize delivery and effectiveness of the cytotoxic payload.

Published Data

In this experiment, a bispecific antibody-drug conjugate (BsADC) targeting prolactin receptor (PRLR) and HER2 was developed to enhance the internalization and efficacy of HER2-based ADCs in breast cancer treatment. PRLR undergoes rapid internalization, while HER2 is slower, and combining these two targets aims to improve drug delivery efficiency. The BsADC showed a higher internalization rate compared to HER2 ADC alone and demonstrated strong binding affinity to both PRLR and HER2. In vitro tests on breast cancer cell lines (BT474 and T47D) revealed that the PRLR-HER2 BsADC had significantly better cytotoxicity compared to single-target ADCs. The study concluded that the dual-targeting BsADC offers improved antitumor activity, primarily due to enhanced internalization facilitated by the PRLR receptor, suggesting it could be a potent therapeutic strategy for HER2-positive cancers.

Fig.2 In vitro cytotoxicity of PRLR × HER2 BsADC on tumor cell lines by CCK8 assay.²

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