Development trend of G protein-coupled receptor ADC drugs

G Protein-Coupled Receptors (GPCR) are a large family of seven types of transmembrane domain proteins expressed on the surface of human cells. These molecules respond to and respond to external stimuli by initiating signal transduction pathways that affect the expression of large gene families. And regulate a series of important physiological processes and functions.

Without these proteins, humans cannot survive. For example, without β-adrenergic receptors, we cannot regulate blood sugar. Without serotonin receptors, we cannot experience happiness. Many physiological functions are related to the signaling pathways regulated by GPCRs. The dysfunction of these pathways can lead to many diseases. Such as cancer, mental diseases, diabetes, cardiovascular diseases, and inflammatory diseases. Therefore, whether in basic scientific research or in the pharmaceutical industry, GPCR protein is a “hot topic” of research.

Antibody-drug conjugate (ADC) mechanism of action: ADC binds to cell surface target receptors, which are internalized to form endosomes and fuse with cell lysosomes. The drug is released from the lysosome and acts on its target (DNA or microtubules) to kill the cell.

Jiang Hualiang, director of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, said: “With GPCRs, you have the world”. So far, more than 800 members of the GPCR protein family have been identified. And the sales of drugs targeting GPCRs account for 27% of the global drug market. The “Sample Drugs” below lists some of the GPCR-related drugs that have been commercialized. Some of which are prescription drugs and others are sold in pharmacies. They have saved lives, relieving pain, and restored health for many patients.

Scientists used X-ray crystal diffraction techniques to elucidate the atomic structure of many GPCRs. Such as β2-adrenergic receptors related to cardiovascular disease and diabetes, adenosine A2A receptors for cancer immunotherapy; Immune system regulation the CCR5 chemokine receptor, P2Y1R. Purinergic receptors related to thrombotic diseases, and D3 dopamine receptors of regulation behavior and mood. All of these are examples of important therapeutic targets for the treatment of human diseases. Their structural information provides a theoretical basis for subsequent drug development.

Data as early as 2017 showed that the U.S. Food and Drug Administration (FDA) approved a total of 475 GPCR-targeted drugs. Accounting for 34% of all drugs approved in the United States. Even though there are so many such drugs on the market, drug research for new drugs targeting more members of this large protein family is becoming more and more intense. The indications of targeted GPCR drugs have also expanded from traditional indications such as hypertension, allergy, anesthesia, and schizophrenia to new areas such as Alzheimer’s disease and obesity. There are currently 321 targeted GPCRs in clinical trials, of which 66 (20%) drugs target new GPCR targets.

In addition to new GPCR targets, new methods for new and old targets are also being explored. So far, most drugs targeting GPCR molecules are small molecules and low molecular weight peptides. However, monoclonal antibody (MAb) drugs have many advantages over small molecules and peptides, especially for oncology and immunological indications. The advantages of targeted GPCRs include:

1.Target specificity and improved safety. (immunogenicity may be a safety issue, but human or humanized monoclonal antibodies can greatly reduce this situation)

2.Long half-life in the body.

3.The ability to eliminate target cells through effector functions. These effector functions include antibody-dependent, cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP).

Single-domain antibodies, bispecific and multispecific antibodies, and antibody-drug conjugates (ADC). These different types of antibodies can target GPCR proteins. Therefore, the pharmaceutical industry is increasingly interested in the development of MAb drugs that target GPCR molecules to treat GPCR-related diseases. At least 74 scientific research projects focus on 37 GPCR molecules. A total of 57 monoclonal antibodies are in the stage of discovery and preclinical research, of which 39 have entered clinical research.

Another type of MoA is antibody-mediated killing a cell expressing a given receptor through a so-called effector function. For example, mogamulizumab (Kyowa Hakko Kirin) is specifically designed to show enhanced ADCC activity on cancer cells expressing CCR4. Due to GPCRs are widely expressed, and proteins mediate many functions, antibodies against GPCRs are often explored for a variety of even seemingly unrelated indications. For example, CytoDyn recently announced that leronlimab, a human immunodeficiency virus (HIV) entry inhibitor against CCR5, also shows promise to alleviate the cytokine storm of COVID-19 and will test it in a phase 2b-3 trial.

Although monoclonal antibodies can kill cancer cells that overexpress the antigen bound to them through effector functions, they can be further enhanced by attaching potent toxins to traditional antibody drugs to form antibody-drug conjugates (ADC). Kind of killing effect. After ADC binds to the target tumor cell, it will be internalized, and then the combined powerful chemical toxin will be released to kill the cell.

The development of ADC has gone through a long and arduous process for more than 20 years. There have been many successes and failures along the way, and many things have been learned through technological innovation and progress. Since ADC is composed of three parts: antibody, toxin, and linking molecule connecting the two, compared with conventional antibodies and other recombinant proteins, its development, production, and testing process is more complicated. However, 8 ADCs have been approved by the FDA (Table 2 above), and half of them have been in the past year. The research and development of ADC are very active even outside the field of oncology, so far, approvals in eight fields have existed.

GPCR targets as drug candidates for ADC drugs

Although GPCRs represent the largest family of protein targets for approved drugs, they have not been widely used as cancer therapeutic targets except for certain endocrine and hormone-responsive tumors. At the same time, even though tremendous progress has been made, the demand for the development of new therapies for cancer treatment is increasing. As people further understand the expression, structure and function of GPCRs in cancer, new therapies for GPCRs will emerge.

GPCRs with increased expression in cancer cells should be particularly attractive as ADC targets. In fact, most GPCRs cause conformational changes after binding to ligands or agonist antibodies, leading to internalization of cells. The rapid internalization of GPCRs is a key feature to turn them into effective ADC drug targets. Fluorescence automated cell sorting (FACS) screens can help scientists discover antibodies with this agonist characteristic, which may be candidates for ADC. In addition, certain tumor cells highly express mutated GPCRs, such as those lacking one or two transmembrane domains. If antibodies specific to such mutant GPCRs can be isolated, they may develop into effective ADC drug candidates, thereby avoiding normal cells expressing normal corresponding proteins.

LGR5 is the first member of the GPCR family to be targeted by ADC, which proves effective tumor efficacy and safety in vivo. In addition, the ADC reduces the size and spread of tumors, and provides improved survival rates in genetically engineered models of intestinal tumorigenesis. The developers hope that clinical trials can further prove their prospects in the near future.

DS-6157 is a “first-in-class” ADC drug targeting GPR20, an isolated GPCR specifically expressed in gastrointestinal stromal tumors (GIST). Different with MoA from TKI , it can be used to treat GIST patients who are resistant to TKI treatment. DS-6157 is currently undergoing phase 1 clinical trials.

LegoChem Biosciences (LCB) selected three strategic GPCRs as drug targets. LCB’s technology is based on a site-specific and plasma-stable ADC platform, using a shorter extra amino acid (CAAX) sequence to create a site-specific binding site at the end of the antibody chain. Prenyl transferase attaches the isoprene substrate to the cysteine ​​residues of the CAAX sequence, creating a binding site to which the ADC linker attaches. Through CAAX-mediated allylation, the site of drug binding and the number of drugs bound to the antibody can be precisely controlled, so that developers can obtain ADC molecules with a specifically defined drug-to-antibody ratio (DAR). Sorrento Therapeutics used this novel ADC format to develop three GPCRs that target CCR2, CXCR3 and CXCR5.

The development of GPCR as an ADC target will face many challenges. In addition to the unique characteristics of GADC as seven transmembrane glycoproteins, it also faces the overall challenge of developing ADC as a therapeutic agent. Obtaining specific and high-affinity antibodies for GPCRs is more difficult because they are insoluble under ordinary conditions and there are only a limited number of extracellular epitopes to evaluate antibodies. However, some companies are developing innovative strategies to screen for antibodies specific to GPCRs. Newer ADC technology platforms and successful clinical experience in ADC development will enable these companies to overcome related challenges.


Hutchings CJ, Koglin M, Marshall FH. Therapeutic Antibodies Directed at G Protein-Coupled Receptors. mAbs 2(6) 2010: 594–606;

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;

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