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Background: The development of antibody therapeutics for imaging and payload delivery is complex, and intact IgG have long half-lives that impact on tumor:blood ratios and tumor penetrance. Smaller molecular weight antibody constructs (eg diabodies) have been developed for improved penetrance into tumor, faster blood clearance, and enhanced tumor: normal tissue uptake, however renal uptake may impact on imaging and therapeutic effects. Through a novel pegylation strategy to surface disulphides, a diabody to TAG-72 (AVP0458) has been generated, and produced under cGMP for a first-in-human clinical trial. Materials and Methods: We have conducted a phase I, open label, first-in-human trial of PEG-AVP0458. The primary study objective was the safety of single dose of I-124 PEG-AVP0458 in patients (pts) with TAG-72 +ve relapsed / metastatic prostate or ovarian cancer. Secondary study objectives were evaluation of the biodistribution, tumor targeting, pharmacokinetics (PK) and immunogenicity of I-124 PEG-AVP0458. Pts were infused with I-124 PEG-AVP0458 (3-5mCi) at one of two dose levels (1mg/m2 and 10mg/m2), and imaged sequentially over a one week period. Safety, PK, and immunogenicity was assessed up to 30 days post infusion. Results: Six pts (1F:5M; age range 62-85yrs; 1 ovarian cancer, 5 prostate cancer) were entered into the study, 3 at each dose level. I-124 PEG-AVP0458 was well tolerated, with no infusion-related adverse events, and no serious adverse events observed. There was consistent biodistribution on PET imaging of I-124 PEG-AVP0458, with no normal tissue uptake. High tumor uptake was evident in metastatic disease in liver and lymph nodes, with lesion uptake seen within 1-2 days post injection. PK analysis showed a T½β of 46.8 ± 12.4 hrs. There was no impact of protein dose on biodistribution, tumor uptake or PK. No immunogenicity to PEG-AVP0458 was evident. Conclusions: I-124 PEG-AVP0458 is safe, and demonstrates excellent, rapid targeting of tumor in vivo, with no specific normal organ uptake, and high tumor: blood ratios. This data demonstrates the feasibility of using pegylated diabodies for imaging and for delivery of radioisotopes (RIT) or cytotoxic drug payloads (ADC) in cancer patients. Citation Format: Andrew M. Scott, Timothy Akhurst, Fook-Thean Lee, Marika Ciprotti, Ian Davis, Andrew Weickhardt, Hui Gan, Pece Kocovski, Nancy Guo, Linda Mileshkin, Scott Williams, Declan Murphy, Rod Hicks, Kunthi Pathmaraj, Sze Ting Lee, Graeme O'Keefe, Sylvia Gong, Maggie Oh, Michael Wheatcroft, Peter J. Hudson. Phase I safety and biodistribution study of 124I-PEG-AVP0458 diabody in patients with TAG-72 positive ovarian and prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT238. doi:10.1158/1538-7445.AM2015-CT238