Anti-RANKL nanobody ALX-0141 shows sustained biomarker inhibition in a Phase I study in healthy postmenopausal Women

Abstract

Introduction: The interaction between RANK/RANKL is critical for the regulation of osteoclastogenesis and bone resorption. Inhibition of this interaction helps restore the balance between bone resorption and formation. ALX-0141, a novel biological agent (Nanobody) that specifically targets RANKL, was studied in a Phase I trial to assess the safety, tolerability, immunogenicity and PK after single injection. Methods: Forty-two healthy postmenopausal women (53-77 years, mean 66 years) were included in this study, which was approved by the local Ethical Committee. Participants received a single SC injection of ALX-0141 (n=31) at 6 dose levels, ranging from 0.003 to 1 mg/kg, or placebo (n=11). PK, PD and safety parameters were monitored for 3 months at the lowest dose level and for more than a year in the higher dose levels. Results: The safety analysis indicated that ALX-0141 was well tolerated. No serious adverse events related to ALX-0141 or dose-limiting toxicity occurred. The frequency of treatment emergent adverse events (TEAE) was similar in placebo-treated subjects (16 events in 7 subjects [64%]) and in subjects treated with ALX-0141 (93 events in 23 subjects [74%]). The most frequent TEAE were musculoskeletal and connective tissue disorders (n=27, reported by 14 subjects) and all TEAE were transient, of mild intensity, and did not result in any study withdrawals. ALX-0141 showed a favourable PK profile, triggering a prolonged PD response. Serum levels of the lead biomarker for bone resorption cross-linking telopeptide of type 1 collagen (CTx-1) decreased rapidly and remained suppressed for up to 390 days after a single SC administration of 1 mg/kg. Conclusions: The results from this Phase I trial indicate that ALX-0141 is a potent RANKL inhibitor that is well tolerated over a wide range of doses. This data supports the further development in bone-resorptive diseases with reduced BMD and increased fracture risk, such as in cancer-related bone diseases, osteoporosis and other disorders.

Unexpected hepatotoxicity in a phase I study of TAS266, a novel tetravalent agonistic Nanobody® targeting the DR5 receptor

“…In the liver, these complexes could potentially bind to DR5 receptors and induce apoptosis in normal hepatocytes, with resultant hepatotoxicity. Notably, no hepatotoxicity and minimal immunogenicity has been reported with bivalent and trivalent Nanobodies ® that have been investigated in non-oncology diseases or healthy volunteers [29][30][31][32]. Interestingly, Holland and colleagues investigated the effect of HAVH autoantibodies on an anti-TNFR1 VH domain antibody (GSK1995057) in healthy human subjects [19].…”

Promising Diagnostic and Therapeutic Approaches Based on VHHs for Cancer Management

“…In a phase I clinical study of 68 Ga-HER2-VHH, 20 patients were free of anti-drug antibodies (ADA) after one injection [18]. A phase I study of ALX-0141, a trimeric format consisting of two identical anti-RANKL humanized VHHs and one anti-albumin humanized VHH, demonstrated that after a single subcutaneous injection in 42 healthy volunteers, no ADAs were found [19]. In summary, the immunogenicity of VHH in humans seems to be relatively low, which prevents one of the main causes of adverse effects, i.e., allergy.…”

Prospects for the computational humanization of antibodies and nanobodies

“…For example, as illustrated above, a dataset of 217 therapeutics with ADA data has been used for validation of antibody-focused computational approaches. In comparison, to our knowledge, ADA data only exists for 10 nanobody therapeutics (Table 2, [56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73]. This discrepancy extends to a differential availability of natural sequence data from which to build models.…”