July 23, 2024

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ADCs Beyond Oncology: Research progress of ADCs in non-anti-tumor fields

ADCs Beyond Oncology: Research progress of ADCs in non-anti-tumor fields


ADCs Beyond Oncology: Research progress of ADCs in non-anti-tumor fields

Antibody drug conjugate ( ADC ) uses the targeting of antibodies to deliver cytotoxins into tumor cells, release highly loaded drugs and drive effective treatment, and has achieved breakthrough success in the field of tumor treatment.

Compared with traditional small molecule drugs, ADCs have obvious advantages in improving targeting and reducing side effects.

According to statistics, 15 ADCs have been approved by the FDA and NMPA for the treatment of various types of tumors, 2 ADCs are in the marketing application stage, and there are more than 1,100 pieces of drug research information ( as of July 5 , 2023 ).

The current breakthroughs in ADC are prompting its gradual expansion into other therapeutic fields, especially in the field of immune disease treatment, where the drugs loaded on ADC are no longer limited to traditional cytotoxins.

This article summarizes the research progress of ADC drugs in the non-tumor field and the selection of payloads.

ADCs Beyond Oncology: Research progress of ADCs in non-anti-tumor fields




Payload: Glucocorticoid Receptor Modulator (GRM)

Antibody targeting E- selectin (E-selectin) and Dexamethasone (Dexamethasone) to construct Dexa-Ab hEsel : E-selectin (CD62E) is an adhesion molecule expressed on activated endothelial cells, but in Not expressed on quiescent endothelial cells.

Synthetic glucocorticoid receptor modulators such as dexamethasone, prednisolone, and budesonide are effective small molecules for the treatment of inflammatory diseases, but they also have serious side effects during the treatment of diseases, Such as high blood pressure, weight gain, diabetes, thinning skin, and osteoporosis.

Methods for attenuating the toxicity of the above drugs while retaining the anti-inflammatory effects have been reported, but these methods have not achieved breakthroughs due to lack of tissue selectivity.

Therefore, new approaches are needed to deliver steroids to sites of inflammation while limiting systemic exposure.


In chronic inflammatory diseases, endothelial cells play an important role in leukocyte recruitment, so they are an attractive target for drug intervention, and inhibition of endothelial cell activation and subsequent leukocyte infiltration can improve chronic inflammatory disease.

The therapeutic effect of the disease. Therefore, targeting glucocorticoids to activated endothelial cells and limiting leukocyte infiltration is an attractive approach.

Dr. Maaike Everts constructed Dexa-Ab hEsel (DAR=2.3) with an antibody targeting E-selectin (E-selectin) and dexamethasone (Dexa) (Figure 1).


ADCs Beyond Oncology: Research progress of ADCs in non-anti-tumor fieldsFigure 1 ADC constructed by targeting E-selectin (E-selectin) antibody and dexamethasone

ADCs constructed by antibodies targeting CD163 and dexamethasone : CD163 belongs to the scavenger receptor family and is an affinity receptor for human hemoglobin-haptoglobin scavengers.

Highly expressed in chronic inflammatory diseases such as atherosclerosis, rheumatoid arthritis and inflammatory bowel disease and on activated macrophages.

Introduce succinic acid on the 21-OH of the end of Dexa to form Dexa -hemisuccinate, activate its terminal carboxyl group and introduce NHS ester to construct Drug-Linker: Dexa-hemisuccinate-NHS, improve the subsequent coupling efficiency; incubate it with the antibody at room temperature (pH 8.3, PBS, ~15 Min), randomly coupled with primary amines (mainly lysine), the DAR value of the constructed ADC-Anti-CD163-Dexa was 4 (Figure 2), and the CD163 performance after coupling High affinity.

In a lipopolysaccharide-induced acute rat inflammation model, an anti-CD163 ADC could inhibit the increase in serum levels of pro-inflammatory cytokines TNFα and IL-1.

However, in healthy rats, the same effective dose of an ADC against CD163 avoided the adverse side effects of systemic dexamethasone treatment, including cortisol suppression, thymic atrophy, and weight loss, suggesting that targeting the therapeutic window through ADCs may Effectively improve. The drug (CYMAC-001) is still in the preclinical research stage.


ADCs Beyond Oncology: Research progress of ADCs in non-anti-tumor fieldsFig. 2 ADC constructed by antibody targeting CD163 and dexamethasone (Dexamethasone)


ADC targeting CD70 and budesonide : Merck and Ambrx used a novel, phosphate-based cathepsin B-sensitive linker (CatPhos) to couple budesonide to a non-natural amino acids on the anti-CD70 antibody (Figure 3). This linker is designed to rapidly release budesonide in lysosomes.


ADCs Beyond Oncology: Research progress of ADCs in non-anti-tumor fields
Figure 3 ADCs constructed with antibodies targeting CD70 and budesonide


ADCs constructed with CD74 – targeting antibodies and fluticasone propionate : Following the prototypes of CD70-targeting antibodies and budesonide-constructed ADCs, Merck and Ambrx developed CD74-targeting ADCs. CD74 is an MHC II protein expressed on antigen-presenting cells and may play a role in autoimmune diseases such as systemic lupus erythematosus.

Fluticasone propionate was conjugated via a pyrophosphate linker to give an anti-CD74 antibody conjugate (Fig. 4a), and studies showed that GILZ (glucocorticoid-induced leucine zipper protein) mRNA was upregulated in CD74-expressing Hut-78 cells .

However, the lack of activity in huCD74-Tg mice led to concerns about payload permeability, so the team focused on finding a glucocorticoid that accumulates in cells when the ADC is catabolized (Fig. 4b).

B cell-dependent activity was observed with anti-CD74-AXC496 for ADCs from the mixed cell culture system of peripheral blood mononuclear cells (PBMCs) against CD74 (Fig. 4c) compared with infiltrating ADCs.


ADCs Beyond Oncology: Research progress of ADCs in non-anti-tumor fieldsFig. 4 ADC constructed by antibodies targeting CD74 and fluticasone propionate

ADC targeting prolactin receptor ( PRLR ) glucocorticoids : PRLR is a member of the type 1 cytokine / hematopoietic receptor superfamily and consists of an extracellular domain, a helical transmembrane portion, and an intracellular domain .

Scientists at Regeneron constructed ADCs targeting PRLR glucocorticoids. To synthesize this ADC, PEG containing an azide group was first attached to Q295 and Q297 of the antibody using transglutaminase.

Then, a protease-sensitive glucocorticoid was coupled to the moiety by click chemistry to obtain an ADC with a DAR=4 (Fig. 5). The ADC showed good targeting in vitro cell experiments, but no in vivo research progress of the ADC was found.


Figure 5 ADCs targeting PRLR glucocorticoids

ADC targeting tumor necrosis factor ( TNFα ) glucocorticoids : Tumor necrosis factor (TNFα) is a pro-inflammatory cytokine mainly produced by macrophages and monocytes and involved in normal inflammatory and immune responses.

Strongly associated with autoimmune and inflammatory diseases such as rheumatoid arthritis, psoriasis and inflammatory bowel disease.

Adalimumab, a TNFα- targeting monoclonal antibody developed by AbbVie , specifically binds to TNF-α and blocks its interaction with cell surface P55 (Tumor Necrosis Factor Receptor-1; TNFR1) and P75 (Tumor Necrosis Factor Receptor- 2; TNFR2).

Therefore, they reasoned that, based on the mechanism of action of adalimumab, immunosuppressive payloads such as glucocorticoids could be targeted for delivery to cells expressing tmTNFα.

The ADC ( ABBV-3373 ) targeting tumor necrosis factor (TNFα) glucocorticoids has shown good effects in the collagen-induced arthritis (CIA) model, and has fewer adverse reactions.

The ADC has entered the phase II clinical research stage, For the treatment of autoimmune-related diseases (NCT03823391).


Figure 6 Molecular structure of ABBV-3373


Payload: Antibiotics

Antibiotic Conjugates Against Staphylococcus aureus: Genentech extends new application of ADC technology to the treatment of infectious diseases.

Staphylococcus aureus is a major bacterial pathogen, and its resistance to β-lactam antibiotics such as methicillin seriously threatens human health.

Although phagocytes such as neutrophils and macrophages can eliminate most bacteria after infection, some pathogens can survive intracellularly, remain resistant to traditional antibiotics, and cause repeated infections.

An antibody-antibiotic conjugate (AAC) targeting intracellular bacteria was identified by screening anti-S. aureus antibodies from infected patients and mice .

Antibodies that recognize bacterial cell wall sugar copolymer β-O-linked N-acetylglucosamine wall teichoic acid (β-GlcNAc WTA) have high specificity for the broadest range of Staphylococcus aureus strains.

An analogue of the bacterial RNA polymerase inhibitor rifampicin served as a payload, was proteolytically released in phagolysosomes, and maintained potent bactericidal activity at lower pH (Fig. 6).

Using the THIOMATM method, rifalogue, a highly potent antibiotic that is activated only after release in lysosomes, was site-specifically coupled to V205C on the light chain of an anti-S. aureus antibody.

AAC is superior to vancomycin in treating bacteremia and eliminating intracellular S. aureus infection in vivo.

AAC offers a unique therapeutic approach against intracellular bacterial infections and is currently in Phase 1 clinical development (NCT03162250).


Figure 7 Molecular structure of RG-7861


Payload: Kinase Inhibitor

Kinase inhibitors such as dasatinib (Sprycel® ; Bristol-Myers Squibb) are effective in the treatment of hematological diseases such as chronic myeloid leukemia, but their lack of selectivity for other kinase family members limits their use in other disease areas such as autoimmunity therapeutic effect on disease.

Off-target effects of kinase inhibitors can produce serious side effects such as pulmonary hypertension, pleural effusion, and neutropenia. Dasatinib can inhibit Bcr-Abl, SRC kinase family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFR-B and other kinases.

Researchers at The Scripps Research Institute and the California Institute for Biomedical Research (Calibr) constructed ADCs to selectively deliver dasatinib directly to T lymphocytes.

They identified the chemokine receptor CXCR4 as an antigen highly expressed on T cells with little or no expression on nonhematopoietic cells.

A conjugate with better therapeutic effect was obtained by linking the dasatinib-linker with the anti-CXCR4 antibody. The linker in ADC adopts PEG4-NH2 non-cleavable linker or enzyme-cleavable linker.

Two-step conjugation of primary amines to anti-CXCR4 mAbs resulted in DAR values ​​close to 3 for both ADCs (Fig. 8).

Both ADCs targeted the delivery of an immunosuppressive dasatinib payload to activated human T cells in vitro and potently inhibited the secretion of pro-inflammatory cytokines.

However, the lack of CXCR4 cross-reactivity limits the evaluation of the preclinical efficacy of the aforementioned ADCs in rodent models of T cell activation and inflammation.


Figure 8 ADC targeting CXCR4



Payload: Liver X receptor (LXR) agonist

Liver X receptor (LXR) is a member of the nuclear receptor superfamily, which plays a key role in the transcriptional regulation of lipid metabolism-related genes, and also has immune response and anti-inflammatory effects.

Development of LXR agonists has been challenging due to toxicity.

Therefore, following the ADC development strategy, we developed an LXR agonist payload to target pathogenic macrophages while avoiding toxicity to normal hepatocytes.

CD11a, also known as LFA-1a or integrin aL chain, has a molecular weight of 180kD and is expressed on all leukocytes, including B lymphocytes, T lymphocytes, neutrophils, eosinophils, basophils, and NK cells , monocytes and macrophages.

It belongs to the integrin family and has the structure of integrin a subunit.

The amino group of the agonist sulfonamide is connected with efalizumab through a linker. The linker uses Phe-Lys dipeptidase to cut the linker, PEG3 regulates water solubility, and an ADC targeting CD11a is designed (Figure 9).


Figure 9 LXR agonist conjugates targeting CD11a



Payload: Phosphodiesterase (PDE4) inhibitor

PDE4 is a key enzyme involved in the degradation of cyclic adenosine monophosphate (cAMP), an important second messenger of inflammatory signals.

PDE4 inhibitors have been developed clinically for the treatment of inflammatory diseases, but dose-limiting toxicities limit their efficacy.

Building on the work on the LXR agonist ADC, scientists at Calibr discovered an ADC: an analogue of the PDE4 inhibitor GSK256066 (small molecule), that uses the same site-specific conjugation chemistry as described above with anti-human CD11a mAb was conjugated (Figure 10a).

The activity of PBMCs stimulated by LPS showed that ADC effectively inhibited the secretion of TNFα compared with unconjugated antibody.

Using a PDE4 inhibitor, an ADC binding to mouse CD11a was prepared with NHS ester analogs with a DAR value of 3 (Fig. 10b).


Figure 10 PED4 inhibitor conjugates targeting CD11a



Payload: Bisphosphonates


Tocilizumab (Actemra®; Roche), an anti-IL-6 receptor antibody, is currently approved for the treatment of rheumatoid arthritis.

Researchers attempted to increase anti-rheumatoid arthritis activity by coupling alendronate, a treatment used to treat bone diseases such as osteoporosis, to tocilizumab drug.

The ADC is a disulfide-linked linker that selectively couples alendronic acid to the oxidized n-glycans of the tocilizumab constant region, which retains anti-IL-6 binding activity (Fig. 11).

In a human macrophage viability assay, the anti-IL-6R alendronate conjugate showed good inhibitory activity compared to non-targeting controls.


Figure 11 Alendronate conjugates targeting IL-6



Summary:  (ADCs Beyond Oncology: Research progress of ADCs in non-anti-tumor fields)


ADCs designed based on the payloads described here are all in the early stages of drug discovery and are still being explored for their application potential in related disease areas.

Some ADCs with therapeutic potential have entered the phase of pivotal clinical research.

To design an ADC drug, factors such as drug efficacy, antibody, linker, cytotoxin, and conjugation technology need to be considered comprehensively.

It is urgent to consider which antibody and payload can suppress adverse reactions while ensuring therapeutic effect and expanding the therapeutic window. and solve the problem.

In the future, differentiated breakthroughs can be sought in terms of linkers, payloads, targets, etc. It is expected that more ADC drugs in the non-anti-tumor field will be approved for marketing in the future, demonstrating their strong clinical value.






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ADCs Beyond Oncology: Research progress of ADCs in non-anti-tumor fields

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