Development of PRLR-based Bispecific ADCs

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.

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. (Goffin, 2017)

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.

What Can We Do for You?

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.

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