Development of PSMA-based Bispecific ADCs

The prostate-specific membrane antigen (PSMA) represents a valuable target for the generation of bispecific antibody-drug conjugates (ADCs) due to its unique characteristics. As a leader in antibody development and ADC preparation, Creative Biolabs takes full advantage of our unique technology platforms to offer bispecific formats ADC development services for our global customers. We focus on ideal target combination, bispecific ADCs design, development, and evaluation to meet all requirements of the clients.

The Overview of PSMA

PSMA is a type II transmembrane protein, which has a 19-amino-acid (aa) intracellular portion, a 24-aa transmembrane portion, and a 707-aa extracellular portion. The extracellular domain was crystallized and determined to fold into three distinct domains: the protease domain (aa 56-116 and 352-591), the apical domain (aa 117-351), and the C-terminal domain (aa 592-750). Based on the structural data, it was demonstrated that PSMA is expressed as a homodimer in a compact three-dimensional (3D) structure. PSMA is an ideal target for antibody-based therapeutics owing to its biological characteristics, including:

1. Considerable (100-fold to 1,000-fold) overexpression on the cell membrane of nearly all prostatic cancer cells compared with normal nontarget expression.
2. Increased expression in advanced-stage and castration-resistant prostate cancers.
3. A large extracellular domain enabling targeting by antibodies and a cytoplasmic domain containing an internalization motif that results in internalization and endosomal recycling.

Fig.1 The structure of PSMA, its binding sites for PSMA ligands, and the most frequently used antibodies. (Maurer, 2016)

Antibody-based Therapeutics Targeting PSMA

To date, only one radiolabeled anti-PSMA antibody targeting an intracellular epitope (7E11) of PSMA has been approved by the FDA. However, 7E11 recognizes the N-terminus (MWNLLH) of the intracellular domain of PSMA and is therefore not able to target viable cells for the delivery of cytotoxic agents. With the development of ADC technology, PSMA was identified as a valuable target antigen for the generation of ADCs against prostate cancer, since it is highly organ-specific, present at the cell surface at all tumor stages, overexpressed in advanced and metastatic disease, not shed into circulation, and internalized after antibody binding. At present, various types of anti-PSMA ADCs (radioimmunoconjugates, immunotoxins, and targeted therapeutic agents) were generated by coupling radionuclides, chemotherapeutic agents, plant toxins, bacterial toxins, zootoxins, or viruses to anti-PSMA monoclonal antibodies (mAbs) or antibody fragments and those anti-PSMA therapeutics are tested in preclinical or clinical trials.

Fig.2 Anti-PSMA ADCs for the targeting of prostate cancer cells. (Wolf, 2013)

In prostate cancer, multiple PSMA-bispecific antibodies are tested in phase I trials. Taking anti-PSMA/CD3 bispecific antibody AMG 160 as an example, AMG 160 binds to both CD3 on cytotoxic T lymphocytes (CTLs) and PSMA found on PSMA-expressing tumor cells. This activates and redirects CTLs to PSMA-expressing tumor cells, which results in the CTL-mediated cell death of PSMA-expressing tumor cells. Numerous studies revealed that AMG 160 induced T-cell activation, prostate cancer-directed cell lysis, and tumor growth inhibition.

Fig.3 Tumor antigens under evaluation to promote engagement with either T effector cells via CD3 or NK cells via CD16. (Trabolsi, 2019)

What Can We Do for You?

The specific 3D structure of the high-glycosylated PSMA homodimer on the cell surface, presenting unique binding epitopes, is lost after isolation with ionizing detergents. Therefore, only mAbs elicited with native PSMA after host immunization with prostate cancer cells, cell membranes, or cell lysates may recognize and strongly bind to PSMA-expressing prostate cancer cells. At Creative Biolabs, great efforts were undertaken to develop high binding affinity mAbs against the extracellular domain of PSMA. Anti-PSMA x CD3, anti-PSMA x CD28, and anti-PSMA x 4-1BB can be combined to generate bispecific antibodies, which can be used for ADC preparation. Moreover, comprehensive bispecific ADC analysis services are also available for you. Please do not hesitate to contact us for more information.

References

1. Maurer, T.; et al. Current use of PSMA-PET in prostate cancer management. Nature Reviews Urology. 2016, 13(4): 226-235.
2. Wolf, P. Anti-psma antibody-drug conjugates and immunotoxins. Antibody-Drug Conjugates and Immunotoxins. Springer, New York, NY, 2013: 255-272.
3. Trabolsi, A.; et al. T cell-activating bispecific antibodies in cancer therapy. The Journal of Immunology. 2019, 203(3): 585-592.

For Research Use Only. NOT FOR CLINICAL USE.