Unlocking the Future: How GPCR-Targeted ADCs Are Changing Cancer Therapy

October 31, 2024
Posted by axispharm

G protein-coupled receptors (GPCRs) are crucial membrane proteins involved in cellular signaling and various diseases, including cancer. Though they are the largest family of drug targets, GPCRs have had limited use in cancer therapies, mainly for endocrine and hormone-responsive tumors. However, as research into GPCR expression and function in cancer grows, these receptors are emerging as promising targets for antibody-drug conjugates (ADCs). By combining antibody specificity with drug cytotoxicity, GPCR-targeted ADCs aim to selectively kill cancer cells and improve therapeutic outcomes.

GPCR-ADC action mechanism

Current Developments in GPCR-Targeted ADCs

Target Identification and Internalization

GPCRs overexpressed in cancer cells are particularly suitable as ADC targets. Most GPCRs undergo conformational changes and rapid internalization when they bind to ligands or agonist antibodies, a key feature for ADCs. High-throughput methods like fluorescence-activated cell sorting (FACS) help scientists find antibodies with these internalizing properties, making them strong ADC candidates. Additionally, some cancer cells express mutated GPCRs, allowing ADCs to target cancer cells while sparing normal cells.

Notable GPCR-Targeted ADC Developments

LGR5: The first GPCR targeted by an ADC, LGR5 showed significant tumor reduction and improved survival in preclinical intestinal cancer models. This success highlights GPCRs as viable ADC targets, with clinical trials anticipated.
DS-6157: This “first-in-class” ADC targets GPR20, a GPCR specifically expressed in gastrointestinal stromal tumors (GIST). Unlike tyrosine kinase inhibitors (TKIs), DS-6157 offers a unique mechanism of action, promising for TKI-resistant GIST patients. DS-6157 is currently in phase 1 clinical trials.
LCB’s Site-Specific ADC Platform: LegoChem Biosciences (LCB) has targeted three GPCRs—CCR2, CXCR3, and CXCR5. Their CAAX platform precisely controls the drug-to-antibody ratio (DAR), creating highly stable and effective ADCs. Sorrento Therapeutics has employed this approach to develop ADCs for these GPCRs.

Challenges in Developing GPCR-Targeted ADCs

Despite the potential, GPCR-targeted ADCs face unique challenges. GPCRs, as seven-transmembrane glycoproteins, have limited extracellular epitopes, complicating antibody targeting and requiring innovative antibody generation techniques. GPCRs are often insoluble under standard conditions, adding complexity to antibody development. However, companies are innovating with new screening techniques to discover GPCR-specific antibodies. Advances in ADC technology and clinical success are helping overcome these obstacles, driving progress in GPCR-targeted ADCs.

Future Prospects for GPCR-Targeted ADCs

With over 350 non-olfactory GPCRs in the human genome, many remain unexplored as ADC targets. Ongoing research aims to identify and validate additional GPCRs for ADC development. Combining GPCR-targeted ADCs with immune checkpoint inhibitors or traditional chemotherapy shows promise for enhanced therapeutic effects. Advances in linker chemistry, payload design, and antibody engineering are expected to further improve GPCR-targeted ADC efficacy and safety, making these treatments increasingly viable.

Conclusion

Targeting GPCRs with ADCs is an exciting and growing field in cancer therapy. Early successes with ADCs targeting LGR5 and GPR20 demonstrate GPCRs’ potential for cancer treatment. While challenges remain, ongoing research and technological progress are paving the way for significant advancements in GPCR-targeted ADCs, opening doors to new, targeted cancer therapies.

Reference

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Gingrich J. How the Next Generation Antibody–Drug Conjugates Expands Beyond Cytotoxic Payloads for Cancer Therapy. ADC Review 7 April 2020.

Kumar KK, Burgess AW, Gulbis JM. Structure and Function of LGR5: An Enigmatic G-Protein Coupled Receptor Marking Stem Cells. Protein Sci.23(5) 2014: 551–565.

Peyton High, Kendra S. Carmon, G protein-coupled receptor-targeting antibody-drug conjugates: Current status and future directions, Cancer Letters, Volume 564, 2023, 216191, ISSN 0304-3835.