ADC Development Services Targeting PSMA

Antibody-drug conjugates (ADC) have become one of the most promising new therapeutic agents for selective killing of tumor cells since it emerged in the past years. To date, several ADCs have already received regulatory approval and many others are in different phases of clinical development.

Creative Biolabs is a leader in the field of antibody development and drug discovery. We have achieved a variety of antibody-related projects as well as the drug synthesis and bio-conjugation. We provide convenient and customized ADCs design and development services that leverage our expertise and knowledge in reagent manufacturing, conjugating and in vitro/vivo analysis.Besides antibody, our standard conjugation services are available for proteins, peptides, and oligonucleotides.

Introduction of PSMA

Prostate-specific membrane antigen (PSMA), also known as FGCP or FOLH, is a type II transmembrane glycoprotein. It is a member of the M28 peptidase family encoded by the PSMA gene. The PSMA gene is located at the short arm of chromosome 11 in human while it is abnormally deleted in prostate cancer. PSMA is expressed on the prostate tissue and carcinoma. PSMA protein consists of an internal portion, a transmembrane domain and an external domain. PSMA plays a critical role in the enzymatic activities serving as a glutamate-preferring carboxypeptidase. Besides, studies results demonstrated that the PSMA has an internalization signal that can facilitate the internalization of the protein on the cell surface into an endosomal compartment. Thus, it is considered as a promising and potential target in the diagnosis and therapy of prostate cancer.

Fig.1 Structural comparison of PSMA and related proteins. (Davis, 2005)

Anti-PSMA ADC in Prostate Cancer

PSMA ADC is an ADC targeting the PSMA, which is composed of a fully human IgG1 monoclonal antibody linked to the microtubule disrupting agent monomethyl auristatin E (MMAE) via a valine-citrulline linker. The ADC has the ability to specifically recognize the PSMA-positive cells, then internalize, and release its cytotoxic drug into the tumor cells. Preclinical trials results demonstrated that the PSMA ADC has potent and selective antitumor activity in advanced prostate cancer models. Besides, a Phase 1 study was performed to evaluate the safety, pharmacokinetics, and preliminary antitumor effects of PSMA ADC in subjects with treatment-refractory prostate cancer.

MEDI3726 (also known as ADC-401) is another novel ADC against the PSMA, which consists of an engineered anti-PSMA antibody J591 site-specifically conjugated to the pyrrolobenzodiazepine (PBD) dimer tesirine. MEDI3726 can specifically bind the PSMA antigen and, once internalized, release the payload to crosslink DNA and induce cell death. In preclinical studies, MEDI3726 showed potent and specific cytotoxicity in PSMA-positive prostate cancer cell lines. In addition, MEDI3726 presented powerful and durable antitumor activity against a variety of PSMA-positive human prostate cancer cell line xenografts. So far, MEDI3726 is being investigated in a phase I clinical trial as a treatment for patients with metastatic castration-resistant prostate cancer (mCRPC).

Fig.2 Structures of MEDI3726 (ADC-401). (Zammarchi, 2017)

MLN2704 is a new ADC designed to target PSMA. MLN2704 contains an anti-PSMA monoclonal antibody conjugated to drug maytansinoid 1 (DM1), a microtubule-depolymerizing compound via an N‑succinimidyl 4-(2‑pyridyldithio) pentanoate linker. MLN2704 has shown significant antitumor activity in mCRPC and osteoblastic prostate cancer metastasis xenograft tumor tissue with no apparent toxicity.

What Can We Do for You?

As one of the leading biologics companies in the area of ADCs, Creative Biolabs offers a comprehensive set of ADCs development services targeting the PSMA from ADCs design, construction to characterization. Our services will facilitate your innovative drug discovery and development progress. If you are interested in our services, please contact us for more information.

Our ADCs development services including:

• ADC Antibody Screening
• DrugLnk™ Custom Synthesis
• Antibody Design and Conjugation
• ADC in vitro Analysis
• ADC in vivo Analysis

References

1. Davis, M. I.; et al. Crystal structure of prostate-specific membrane antigen, a tumor marker and peptidase. Proceedings of the National Academy of Sciences. 2005, 102(17): 5981-5986.
2. Zammarchi, F.; et al. ADCT-401/MEDI3726, a novel pyrrolobenzodiazepine (PBD)-based antibody-drug conjugate (ADC) targeting PSMA-expressing prostate cancers. CANCER RESEARCH. 2017, 615.

For Research Use Only. NOT FOR CLINICAL USE.