Clinical Translation of a Caveolae Targeting Antibody for Enhancing Cancer Drug Delivery

PROJECT SUMMARY
This proposal aims to develop a novel caveolae targeting antibody for rapid clinical translationIts long term
objective is to develop the caveolae pumping systeman active transendothelial transport pathwayto provide
an effective solution to the delivery and toxicity problem of systemically administered chemotoxinsWork will be
based on the current proprietary mouse monoclonal antibody that targets a truncated form of Annexin AmAnnAthat is concentrated in the endothelial cell caveolae of tumor vasculaturePrevious work has
demonstrated mAnnAto be the first antibody to penetrate solid tumors activelyrapidlyand specificallyand
concentrate attached cargo directly into target tissueHumanization of mAnnAis expected to yield a variant
with similar binding affinitystabilityand purity that can then be used for further commercial development to
generate novel immunoconjugates to treat many forms of primary and metastatic cancersWe hypothesize that
enhancing precision delivery will confer significant survival advantages for patients through the antibodyandapos s ability
to concentrate chemotoxins directly into solid tumors and metastatic lesionsthus sparing exposure to healthy
tissuesThe overall objective of this Phase I application is to advance translational studies of mAnnAthrough
development and selection of a humanized antibody with optimized binding affinity and therapeutic potentialIn
Aimantibody humanization will proceed using CDR grafting technologyproducingvariantsSelection of
hAnnAcandidates with binding affinities similar to mAnnAwill be performed using ELISA and surface plasmon
resonance analysisIn AimhAnnAvariants will be further screened by their ability to retain key biophysical
propertiesbinding affinitystabilitypurityafter chemical conjugationThe therapeutic potencies of the topvariantsin the form of therapeutically active immunoconjugateswill be validated in vivo using a metastatic
model of breast cancerThe proposed study is highly significant because a first in class humanized AnnAantibody with minimized immunogenicity could deliver therapeutic cargo precisely across in vivo barriers and
concentrate them inside tumorsand thus obviate the current reliance on passive transvascular deliveryIf
successfulit will create the first precision drug delivery platform based on the caveolae pumping systemThe
resulting lead hAnnAantibody will be advanced in an STTR Phase II project for further commercial and
preclinical developmentpharmacological and toxicological testingand other studies needed for IND filing and
clinical utilityPotential partnering or out licensing points for pharmaceutical company facilitation of
commercialization of hAnnAcan occur after each completed phase of the overall project PROJECT NARRATIVE
As the first antibody to be pumped by an active transport mechanism specifically into solid
tumorsmAnnArepresents a major paradigm shift in drug delivery strategies for the treatment
of human solid cancersTo advance this antibody towards clinical translationCavatar is
developing a novel humanized version of mAnnAthat will exhibit the same potential to rapidly
and precisely deliver conjugated drugs and radioimmunoconjugates into primary tumors and
metastatic lesions following intravenous injectionand thus enhance therapeutic potency at low
dosesExploiting an active cellular transport pathway to improve precision delivery of anticancer drugs directly into solid tumors could significantly increase their therapeutic potency and
reduce toxicity for patientsThis novel approach is broadly applicable to improving treatments
for many forms of both primary and metastatic cancers