This is a two-part study. The first part (Stratum I) is an open-label, dose escalation, safety, tolerability and pharmacokinetic study, where active study drug (PF-04523655) will be given to all patients who participate. Stratum I will determine the maximum tolerated dose and any dose-limiting toxicities. The second part (Stratum II) is a prospectively randomized, multi-center, double-masked, dose ranging study evaluating the efficacy and safety of PF-04523655 alone and in combination with ranibizumab versus ranibizumab alone in patients with DME.

Patients will be enrolled concurrently according to one of two sets of criteria designated as Stratum I and Stratum II.

1. Stratum I will enroll up to 24 subjects with low vision, inclusive of possible intermediate doses, in up to 4 cohorts of 3-6 evaluable subjects.
2. Stratum II will enroll approximately 240 subjects with DME 1:1:1:1 in up to 4 cohorts of 60 evaluable subjects.

Key Stratum I Inclusion Criteria:

1. Visual acuity in the study eye ≤ 20/200.
2. Low visual acuity is the result of an irreversible condition affecting the posterior segment of the study eye.

Key Stratum I Exclusion Criteria:

1. History of vitrectomy.
2. History of IVT injection in study eye within last 6 months.
3. History of vitreous hemorrhage, retinal detachment, or invasive trauma in study eye.
4. History of uveitis or endophthalmitis in either eye.
5. Any active inflammatory condition in study eye.
6. Received any drugs known to cause optic nerve or retinal toxicity within 14 days prior to dosing.
7. Any medical condition, concomitant therapy or previous incisional or laser surgery that, in the opinion of the Investigator, would preclude IVT injection in the study eye.
8. Intraocular pressure in either eye ≥25 mmHg on maximal medication.
9. Cataract surgery and laser corneal surgery within 3 months prior to dosing in the study eye and all other intraocular surgeries at any time.
10. Participation in a concurrent interventional study within 30 days prior to dosing.

Key Stratum II Inclusion Criteria:

1. History of diabetes mellitus (Type 1 or Type 2).
2. Retinal thickening secondary to the edema caused by diabetes mellitus.
3. Best corrected visual acuity (BCVA) of 20/40 or worse and up to 20/320 or better in the study eye at Screening.
4. Standard of care treatment for DME can be withheld for at least 90 days after the subject has enrolled in the study (study eye only).

Key Stratum II Exclusion Criteria:

1. History of panretinal photocoagulation within 6 months or macular laser photocoagulation within 3 months of prior to dosing in the study eye.
2. Any IVT injection therapy performed in the study eye within 3 months prior to dosing.
3. Iris neovascularization, vitreous hemorrhage, tractional retinal detachment, vitreomacular traction, clinically significant epiretinal membrane or clinically significant preretinal fibrosis involving the macula in the study eye.
4. History of vitreoretinal surgery or incisional glaucoma surgery in the study eye.
5. Prior intraocular surgery or corneal laser surgery, performed within 3 months prior to dosing in the study eye.
6. Received any drugs known to cause optic nerve or retinal toxicity within 14 days prior to dosing.
7. High risk (in the opinion of the Investigator) proliferative diabetic retinopathy (PDR) in the study eye.
8. Current infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye.
9. Monocular subjects.
10. History of idiopathic or autoimmune uveitis in either eye.
11. Aphakia or absence of the posterior capsule in the study eye.
12. Structural damage to the center of the macula in the study eye likely to preclude improvement in visual acuity following the resolution of macular edema.
13. Uncontrolled glaucoma in either eye.
14. Spherical equivalent of the refractive error in the study eye of more than -8 diopters myopia.
15. Use of corticosteroids that, in the Investigator's opinion, may change the status of the subject's diabetic retinopathy in the study eye.