Targeted Delivery of an Anti-inflammatory PDE4 Inhibitor to Immune Cells via an Antibody–drug Conjugate

Abstract

SIGNIFICANCEPDE4 inhibitors are clinically validated molecules with considerable efficacy but relatively low safety profile in treating chronic inflammatory diseases. Therefore, the potential expansion of clinical indications of these molecules is relatively unexplored.Bringing to bear medicinal chemistry and bio-conjugation methods, we generated αhuCD11a-PDE4 and its mouse equivalent αmuCD11a-PDE4, which target the pan-immune cell surface antigen CD11a and demonstrated potent in vitro suppression of inflammation that is explicitly receptor-dependent. Pharmacokinetic and pharmacodynamic analysis of αmuCD11a in vivo revealed translation of these effects. With antibody-based therapies becoming a mainstay in the treatment of inflammation, this study provides critical validation for a new paradigm which could lead to second generation PDE4 inhibitors with an improved safety and efficacy.

Current possibilities of liquid chromatography for the characterization of antibody-drug conjugates

“…The antibody part has a key role in selective target cell recognition, while the conjugated potent cytotoxic drug is responsible for the effective elimination of the target cells [1,2]. This concept lead to new therapy approaches in numerous oncological [3][4][5] and infectious indications [6,7] as well as for arthrosclerosis [8], anti-inflammatory treatments [9] and immunosuppression [10]. Currently, more than 60 CECs are in clinical trials and this number is expected to increase in the future [11][12][13].…”

Therapeutic applications of genetic code expansion

“…2 ) [ 66 ]. The synthesis of chemical defined CXCR4-auristatin ADC, anti-CD11a IgG conjugated with liver X receptor (LXR) agonists or phosphodiesterase 4 (PDE4) embraced the same strategy [ [67] , [68] , [69] ]. These ADCs not only showed significant effects in in vivo disease models but also reduced unwanted side-effects due to the improvement of drug specificity.…”

Antibody Conjugates-Recent Advances and Future Innovations

“…Genentech has pioneered antibody-antibiotic conjugates [41,42] to target intracellular Staphylococcus aureus within host cells. Others have leveraged the internalization mechanism of antibodies to deliver immunosuppressive, cardiovascular or metabolic disorder small molecule drugs to specific cells using cell surface targets such as E-selectin [43], CD11a [44,45], CD25 [46], a3(IV)NC1 [47], CXCR4 [40,48], CD45 [49], CD70 [50], CD74 [51], and CD163 [52,53]. Examples of linker payloads as well as formulation and delivery challenges for non-oncology indications are discussed below.…”

“…Using an anti-CD11a antibody conjugated to an LXR (Liver X Receptor) agonist f, researchers were able to target macrophages to reverse cholesterol transport and reduce inflammation without negatively affecting hepatocytes, which have previously shown on-target toxicity with LXR agonists [44]. Antibody targeting CD11a was also used to selectively deliver a known PDE4 (Phosphodiesterase 4) inhibitor (GSK256066, g) and reduce inflammatory cytokine production, showing promise for the treatment of chronic inflammatory conditions with a more optimal therapeutic index [45]. In a similar fashion, dasatinib As with other oncology examples, nicotinamide phosphoribosyltransferase (NAMPT) inhibitors d have not succeeded in the clinic due to low therapeutic index with limiting toxicities, but exploitation of ADC targeted delivery of NAMPT inhibitors provides an outlet for these potent payloads [101] in preclinical studies.…”

“…This growing trend exerts pressure on linker-payload design and conjugation methods in addition to the properties of the parental antibodies, as well as on formulation and device development. The current pre-clinical data for non-oncology ADCs suggest that the ADC doses might not be significantly lower than those for antibodies [41,45,47,52]. The clinical efficacy and therapeutic index of the non-oncology ADCs will ultimately determine the dose requirement and the appropriate drug product concentration.…”