AMB-055 for PKD

Disease and Prevalence

The two most important hereditary kidney cystic diseases are autosomal dominant polycystic disease (ADPKD) and autosomal recessive polycystic disease (ARPKD). Of the two, ARPKD is more rare and severe - affecting ~1:20,000 births and with mortality approaching 30% during the neonatal and first year of life. Newborns may present with a “Potter” phenotype, consisting of massive kidney enlargement, pulmonary hypoplasia, and contracted limbs with club feet. Early age morbidity and mortality are primarily related to pulmonary hypoplasia and thoracic compression due to enlarged kidneys. Kidney pathology includes multiple microcysts within the renal cortex and medulla and lack of corticomedullary differentiation. After birth, fluid-filled cystic lesions become larger and increase in number, followed by progressive renal insufficiency and arterial hypertension. With aging, hepatobiliary disease involving abnormal bile duct development and cysts present, and hepatic fibrosis and portal hypertension become serious complications (1-3).

ADPKD is one of the most common, potentially lethal, monogenic diseases found in humans. The diagnosed prevalence is estimated at ~4 in 10,000 (4,5). Accordingly, there are ~400,000 diagnosed patients in US and Europe and ~3 million worldwide. It is generally adult-onset and characterized by bilateral, progressive enlargement of fluid-filled tubular epithelial cysts occurring in all nephron segments and collecting ducts resulting in massively enlarged kidneys and eventually leading to renal interstitial fibrosis and end-stage renal disease (ESRD) (6).

Pathogenesis and AMB-055 Mechanism of Action

ARPKD is caused by mutations in the PKHD1 (polycystic kidney and hepatic disease 1) gene (7).  PKHD1encodes the fibrocystin/polyductin (FPC) protein which is expressed on cilia and centromers of renal tubular epithelial and bile duct cells (8). The function of fibrocystin is not fully understood, but it appears to regulate the proliferation and differentiation of the cells lining the kidney tubule and, when defective, can lead to tubule dilation and cystic disease (9).  The vast majority of ADPKD (80%) is due to mutations in PKD1 which encodes polycystin-1 (PC1).  It is a 467 kDa receptor-like integral membrane protein containing a long N-terminal extracellular domain and is thought to be involved in cell–cell-matrix interactions and also calcium homeostasis.  Despite the identification of the causative genes responsible for ADPKD and ARPKD, the precise function of these genes and their protein products is still unclear (6).  Studies from multiple labs and multiple models demonstrate that ADPKD and ARPKD share common phenotypic abnormalities and intersecting signaling pathways whose disruption leads to cyst formation (6).

Fibrocystin-defective epithelial cells (e.g. biliary, renal) promote macrophage recruitment and differentiation to profibrogenic M2-type macrophages (10). Indeed, over the last 5-10 years, a pathogenic role for the wound-healing type (M2-like) macrophages in ARPKD has become evident (11). A normal function of renal M2-like macrophages is to promote tissue remodeling and regeneration in injuries, but in PKD, M2 macrophage function, influenced by CSF1, is dysregulated. And these cells are capable of stimulating proliferation and microcyst formation ex vivo.  See Figure below from Kidney Int. 83: 855, 2013 depicting M2 macrophage infiltration including within cysts:

As well-established in the literature, CSF-1 acting at the CSF-1R is a prime regulator of monocyte/macrophage differentiation and activity. Indeed, there is an increased concentration of macrophages in human kidneys from ARPKD and ADPKD patients as well as in cystic kidneys of rodent models of ARPKD and ADPKD.  And a subset of M2 macrophages is strongly associated with renal fibrosis in both human and experimental diseases.  Hence, AMB-055, as a inhibitor of CSF-1R activity, is well-positioned as a novel treatment approach for both ARPKD and ADPKD.  Additional supportive data includes the following:

  • Depletion of macrophages (including M2-type) in the cpk/cpk mouse model of ARPKD results in reduced kidney pathology and improved BUN levels (11).

  • Inhibiting CSF1/CSF1-receptor signaling with a CSF1R kinase inhibitor (GW2580) dosing regimen reduced local macrophage proliferation and renal cyst formation in 2 mouse models of cystic disease (12).

  • In the human renal diseases, macrophage accumulation significantly correlates with both the degree of glomerulosclerosis and the extent of interstitial fibrosis and tubular atrophy and progression coincides with a switch to an M2-like phenotype (11, 13).

LifeMax intends to further study the efficacy of AMB-055 in an animal model(s).

Current Treatment & Unmet Need

There are no approved pharmacotherapies – nor late-stage clinical candidates in development - for ARPKD and no macrophage-modulating therapies for ADPKD.  Treatment is symptomatic and infants may require peritoneal dialysis and many patients proceed to dialysis and end-stage renal disease and become candidates for kidney and/or renal transplantation. Hence, there is tremendous unmet need in ARPKD. Tolvaptan in ADPKD has limited efficacy and substantial side effects and a black box warning of hepatocellular injury and does not appear to impact fibrosis which is considered critical in renal failure.

AMB-055 Differentiation

With its generally good clinical safety and tolerability, and in vivo proof-of-mechanism (14), AMB-055 has the potential to become both a First-in-Class therapeutic for the treatment of ADPKD and ARPKD, and First-Approved for ARPKD.


  1. Melit LE et al., Medicine 2019; 98:44

  2. Sweeney WE et al., Polycystic Kidney Disease, Autosomal Recessive. Updated 2019Feb14 in: Adam MP et al., editors. GeneReviews. University of Washington, Seattle

  3. Williams SS et al., Pediatr. Nephrol. 2008; 23:733–741

  4. Willey CJ et. al., Kidney Dis. 2019; 5:107–117

  5. Willey CJ et. al., Nephrol. Dial. Transplant 2017; 32:1356–1363

  6. Sweeney WE and Avner ED, Pediatr. Res. 2014; 75:148–157

  7. Ward CJ et al., Nat. Genet. 2002; 30:259–269

  8. Ward CJ et al., Mol. Genet. 2003; 12:2703-2710

  9. Pazour GJ et al., Cell Signal 2019; 69:109519

  10. Locatelli L et al., Hepatology 2016; 63:965

  11. Swenson-Fields KI et al., Kidney Int. 2013; 83:855

  12. Zimmerman KA et al., JASN 2019; 30(10):1841-1856

  13. Tang, PMK et al., Nature Reviews, Nephrology 2019; 15:144-158

  14. Papadopoulos KP et al., Clin. Cancer Res. 2017; 23:5703

AMB-055 is the human monoclonal antibody (mAb) against the CSF-1R. Available data indicates that CSF1-responsive macrophages contribute to cyst formation and fibrosis in both autosomal recessive polycystic disease (ARPKD) and autosomal dominant polycystic disease (ADPKD).  Accordingly, it may be positioned as a treatment for both indications.  There are no effective nor approved therapies for ARPKD, and an approved drug for ADPKD – Tolvaptan – has a black box warning and does not affect the fibrotic component of PKDs which is the primary determinant of ultimate renal failure.

AMB-055 is mechanistically and clinically well-positioned as a first-in-class and first-approved therapeutic.


Treating Orphan Diseases With Few or No Options.


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