July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Stability and activity profiles of anti-complement factor D fragments translate across in vitro and in vivo studies to support long-acting delivery approaches
Author Affiliations & Notes
  • Kelly M Loyet
    Genentech, Inc., South San Francisco, California, United States
  • Philip Hass
    Genentech, Inc., South San Francisco, California, United States
  • Wendy Sandoval
    Genentech, Inc., South San Francisco, California, United States
  • Ashley Morando
    Genentech, Inc., South San Francisco, California, United States
  • Peter Liu
    Genentech, Inc., South San Francisco, California, United States
  • Whitney B Shatz
    Genentech, Inc., South San Francisco, California, United States
  • Leslie Dickmann
    Genentech, Inc., South San Francisco, California, United States
  • Margaret Kenrick
    Genentech, Inc., South San Francisco, California, United States
  • Jeremy Good
    Genentech, Inc., South San Francisco, California, United States
  • Teresa Davancaze
    Genentech, Inc., South San Francisco, California, United States
  • Alyssa Morimoto
    Genentech, Inc., South San Francisco, California, United States
  • Robert Kelley
    Genentech, Inc., South San Francisco, California, United States
  • Justin Scheer
    Genentech, Inc., South San Francisco, California, United States
  • Footnotes
    Commercial Relationships   Kelly Loyet, Genentech, Inc. (E); Philip Hass, Genentech, Inc. (E); Wendy Sandoval, Genentech, Inc. (E); Ashley Morando, Genentech, Inc. (E); Peter Liu, Genentech, Inc. (E); Whitney Shatz, Genentech, Inc. (E); Leslie Dickmann, Genentech, Inc. (E); Margaret Kenrick, Genentech, Inc. (E); Jeremy Good, Genentech, Inc. (E); Teresa Davancaze, Genentech, Inc. (E); Alyssa Morimoto, Genentech, Inc. (E); Robert Kelley, Genentech, Inc. (E); Justin Scheer, Genentech, Inc. (E)
  • Footnotes
    Support  Genentech, Inc., South San Francisco, CA, provided support for the study and participated in the study design; conducting the study; and data collection, management, and interpretation
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 226. doi:
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      Kelly M Loyet, Philip Hass, Wendy Sandoval, Ashley Morando, Peter Liu, Whitney B Shatz, Leslie Dickmann, Margaret Kenrick, Jeremy Good, Teresa Davancaze, Alyssa Morimoto, Robert Kelley, Justin Scheer; Stability and activity profiles of anti-complement factor D fragments translate across in vitro and in vivo studies to support long-acting delivery approaches. Invest. Ophthalmol. Vis. Sci. 2018;59(9):226.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Long-term physiological stability and activity are necessary for a therapeutic dosed to the eye for long-acting therapeutic delivery in the eye. We tested the in vitro and in vivo physiological stability and target-binding properties of anti-complement factor D humanized antibody fragment (AFD; FCFD4514S, lampalizumab) and two variants (AFD.v8 and AFD.v14) that were developed as alternatives to AFD for less frequent dosing options.

Methods : AFD binding activity and stability were assessed in aqueous humor from a subset of Mahalo trial patients with Geographic Atrophy secondary to age related macular degeneration (NCT01229215; n=14 monthly dosed and n=9 bimonthly dosed) using immunoassay, surface plasmon resonance, and mass spectrometry methods. AFD, AFD.v8, and AFD.v14 were assessed for in vitro stability and binding activity in human vitreous humor (pooled samples from nine patients aged ≥ 60 years undergoing surgery for macular hole or macular pucker) at 37°C over 16 weeks, or in vivo in New Zealand White rabbits over 28 days, together with pharmacokinetic determinations.

Results : AFD specific binding was > 85% through 30 days and deamidation was < 3% through 60 days in Mahalo patient aqueous humor, similar to that seen with in vitro AFD stability and binding activity in vitreous humor from humans and rabbits in vivo. AFD.v8 and AFD.v14 target binding, stability, and pharmacokinetic parameters were similar to those of AFD.

Conclusions : In vitro and in vivo studies in humans and rabbits allowed observation and translation of physiological stability and activity for AFD and its two variants. AFD.v8 and AFD.v14 demonstrated potency and pharmacokinetics comparable to AFD. These findings, along with the previously demonstrated improved solubility of AFD.v8 and AFD.v14, provide proof-of-concept for developing long-acting therapeutic variants of similar agents.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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