Background: HuMax-Axl-ADC is an antibody-drug conjugate (ADC) that specifically targets Axl-expressing tumor cells. Aberrant expression of Axl, a receptor tyrosine kinase, has been described in solid and hematological malignancies, in both primary tumors and metastasis. Expression and activation of Axl is associated with poor clinical prognosis in cancers of the lung, pancreas, esophagus and breast. Moreover, Axl expression has been implicated in resistance to both chemotherapy and targeted therapy. Although the mechanism behind Axl activation in cancer is not fully understood, activation through the Axl ligand Gas6 has been implicated in at least some cancers. At the cellular level, Axl is involved in tumor cell adherence, migration and epithelial-to-mesenchymal transition. Methods: A panel of Axl-specific ADCs was generated by conjugating human Axl antibodies with the microtubule disrupting agent monomethyl auristatin E (MMAE), through a protease-cleavable linker. Axl-ADCs were functionally characterized in vitro, and the anti-tumor activity was tested in vivo using xenograft models. Results: Axl-ADCs demonstrated high affinity binding to Axl and efficiently induced cytotoxicity in vitro, which was dependent on both Axl expression and conjugation with MMAE. In a lung cancer xenograft model, Axl ADCs were shown to have potent anti-tumor activity in vivo. The most potent Axl-ADCs, including HuMax-Axl-ADC, induced complete tumor regression upon treatment with a single dose of 1 mg/kg. HuMax-Axl-ADC also strongly inhibited tumor growth in a xenograft model that showed high endogenous expression of Gas6. This is in line with our observation that HuMax-Axl-ADC does not compete with Gas6 for Axl binding. Importantly HuMax-Axl-ADC was able to induce tumor regression in PDX models that, similar to many human tumor biopsies, showed Axl expression in only a subpopulation of tumor cells Conclusions: HuMax-Axl-ADC is a novel ADC that shows potent anti-tumor activity in solid cancer xenograft models. The results obtained in preclinical studies support further development of HuMax-Axl-ADC for the treatment of solid cancers.