Evaluation of the Glycan Receptor Ligand Mannan as a Potential Mitigation Strategy for Non‐Target‐Related Toxicities of Antibody‐Drug Conjugates
Authors: Ciurlionis Rita , Mantena Srinivasa R , Dunn Christina J , Klapczynski Marcin , Buck Wayne R , van Vleet Terry R 
Published: November 2023

Antibody‐drug conjugate (ADC) uptake via the mannose receptor or other glycan receptors has been proposed as a possible mechanism of some non‐target‐related toxicities. Mannan, a natural polymer of mannose found in yeast cell walls, is serologically similar to structures found on mammalian glycoproteins including immunoglobulins and has been shown to limit the uptake of ADCs in cellular models. Mannan binds to cell surface glycan receptors and is anticipated to alter the tissue distribution of ADCs which can also bind to those receptors via their glycosylation sites. In order to test the tolerability of systemic mannan administration to support its potential use as a mitigating agent that would limit non‐specific ADC uptake, male CD1 mice were dosed up to 5 days with daily IV bolus doses of mannan (from S.cerevisiae) formulated in normal saline at 0, 30, 100, 300 and 1000 mg/kg (n=4/group). All mice in the 30 mg/kg dose group survived and mannan was well tolerated at this dose. Doses of 100 mg/kg and greater were not tolerated and either morbidity or mortality was noted within 1 hour of dosing. The nature of the clinical signs and timing relative to dosing suggest anaphylaxis‐like shock, documented in certain strains of mice with IV mannan administration, or plasma volume expansion as possible causes of death. Histopathological review showed unique retinal changes in only the non‐tolerated dose groups. The changes were characterized by cytoplasmic vacuolation of the inner portion of the inner nuclear layer. Staining for AP‐2 alpha (Activating Enhancer Binding Protein 2 Alpha), an amacrine cell‐specific marker in the inner portion of the inner nuclear layer, confirmed that the vacuolation was indeed restricted to these amacrine cells.

Mannose supplementation has been used in other clinical settings such as for correction of hypoglycosylation resulting from mutations in phosphomannose isomerase (MPI) in congenital disorder of glycosylation. It has been previously reported that female C57BL/6J mice hypomorphic for MPI, that were supplemented with mannose in drinking water at 2–5% during gestation, produced embryos with severe developmental abnormalities resulting in high lethality. Surviving pups showed severe eye defects including an observed decrease in AP‐2 staining in the inner nuclear layer of the retina. Mannose supplementation during adulthood after eye development for 4–6 months in both WT mice and mice hypomorphic for MPI was not associated with similar defects. Differences in route, dose, monomeric vs. polymeric form of mannose and strain of mice could explain why a similar phenotype in retina was observed when mannan was dosed in adult mice in the current study and suggests caution should be observed even in adulthood when mannan supplementation is considered clinically.

Support or Funding Information

RC, SM, CD, MK, WB, TV are employees of Abbvie.

The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.