Notes
PF-06263507 (A1-mcMMAF / "A1-mafodotin") = humanized anti-5T4 (TPBG) IgG1 antibody PF-06281192 conjugated via a NON-CLEAVABLE maleimidocaproyl (mc) linker to MMAF (monomethyl auristatin F), random interchain-cysteine conjugation, DAR 4. MMAF is a charged, membrane-impermeable, NON-bystander auristatin (released catabolite Cys-mcMMAF). Sole clinical trial: FIH Phase 1 dose-escalation NCT01891669 (Shapiro et al., Invest New Drugs 2016; PMC5418317), N=26 across 0.05-6.5 mg/kg IV Q3W; MTD/RP2D = 4.34 mg/kg (n=6). No objective responses. Trial TERMINATED 2015-06-23; CT.gov states termination was for company portfolio reprioritization "not due to any safety concerns," but the dose-limiting toxicities were OCULAR: G3 photophobia at 4.34 mg/kg, and G2 keratitis + G1 limbal stem cell deficiency at 6.5 mg/kg.
OCULAR (the qualifying signal; classic off-target auristatin-F corneal/ocular-surface toxicity): treatment-related any-ocular = 38.5% (10/26) per publication. Leading PTs (all-cause CT.gov posted results, N=26): photophobia 26.9%, dry eye 23.1%, blurred vision 19.2% (treatment-related 11.5%), eye pain 15.4%, lacrimation increased 7.7%, vitreous floaters 7.7%, conjunctivitis 7.7%, and a corneal cluster each at 3.8% (keratitis G2, keratopathy, corneal deposits, limbal stem cell deficiency G1; CT.gov also lists eye pruritus, eye swelling, lacrimation decreased each 3.8%). G3+ ocular: G3 photophobia (1/26) + G3 eye pain (1/26) = each 3.8% (up to 7.7% if distinct patients); no G4/5 ocular. All ocular AEs reversible (G3 photophobia & G2 keratitis resolved without sequelae; managed with artificial tears/steroid drops). Dose-dependent (RP2D 4.34 cohort: photophobia 3/6, blurred vision 2/6, keratopathy/lacrimation each 1/6). Classified ocular_surface_subtype = Corneal (off-target).
CAUSALITY/DENOMINATOR CONVENTION: ocular summary fields use all-cause CT.gov posted results (N=26, to match sibling PF entries and capture the full PT list); non-ocular toxicity_rows use treatment-related figures from the peer-reviewed publication (grade-resolved), with all-cause CT.gov noted per row. N=26 is the pooled FIH escalation population (no expansion cohort); line_context tagged "RP2D" represents this primary cohort (RP2D 4.34 mg/kg n=6). Neutropenia not reported (only leukopenia 3.8% all-cause). No treatment-related pulmonary or infusion-reaction signal (all-cause dyspnoea 19.2% and cough 19.2% are likely disease-related in this advanced-cancer population; auristatins are not classically pulmonary-toxic).
PAYLOAD physchem (PubChem CID 10395173, computed): MW 731.97, XLogP 2.1, TPSA 167, HBD 4, HBA 9; bystander = No. payload_logd_7_4 and payload_pka left blank (no single clean source); MMAF is anionic/zwitterionic at pH 7.4 (free C-terminal phenylalanine carboxylate), which underlies its low membrane permeability and non-bystander behavior. LINKER (ADCdb LIN0TAFAV, maleimido-caproic acid reagent form): SMILES O=C(O)CCCCCN1C(=O)C=CC1=O, C10H13NO4, MW 211.22, TPSA 74.68, xLogP 0.56; non-cleavable. ADCdb cross-refs: ADC DRG0KHFFZ, linker LIN0TAFAV, payload PAY0QLDVX (TTD D03JZC; ChEMBL CHEMBL4297804). Sources: ADCdb (composition/linker physchem), Shapiro et al. Invest New Drugs 2016 / PMC5418317 (clinical, treatment-related AEs with grades, CTCAE v4.03), ClinicalTrials.gov NCT01891669 posted results (all-cause AE table, dose cohorts), PubChem CID 10395173 (payload).