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<input type="email" aria-label="Sender Email Address" placeholder="email@example.com" id="email-from" class="email-from" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="256">
</div>
<div class="action-panel-control-wrap">
<label for="email-citation-format" class="action-panel-label">
Format:
</label>
<select id="email-citation-format" name="citation-format" class="action-panel-selector email-citation-format">
<option selected="selected" value="summary">Summary</option>
<option value="summary-text">Summary (text)</option>
<option value="abstract">Abstract</option>
<option value="abstract-text">Abstract (text)</option>
</select>
</div>
<div class="include-supplemental-container">
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
</div>
<div class="form-field recaptcha ">
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
</div>
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="send">
Send email
</button>
<button class="action-panel-cancel"
aria-label="Close 'Email citations' panel"
ref="linksrc=close_email_panel"
aria-controls="email-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="cancel">
Cancel
</button>
</div>
<input type="hidden" name="email-search-details" value="" />
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524" />
</form>
</div>
</div>
<div id="collections-action-panel"
class="collections-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-collections-open-panel-enabled="false"
data-collections-open-panel-url-hash="#open-collections-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to Collections
</h3>
<form id="collections-action-panel-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-myncbi-max-collection-name-length="100"
data-add-to-collection-max-amount="1000"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
<input type="hidden" name="csrfmiddlewaretoken" value="3QcQeKVISpmCzpC84Mm8o8f3Ra5rC5v4kDWVRAo4s096tQIYH5ZaSgLHpeNDvG3o">
<div class="choice-group" role="radiogroup">
<ul class="radio-group-items">
<li>
<input type="radio"
id="collections-action-panel-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_new">
<label for="collections-action-panel-new">Create a new collection</label>
</li>
<li>
<input type="radio"
id="collections-action-panel-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_existing">
<label for="collections-action-panel-existing">Add to an existing collection</label>
</li>
</ul>
</div>
<div class="controls-wrapper">
<div class="action-panel-control-wrap new-collections-controls">
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label>
<input
type="text"
name="add-to-new-collection"
id="collections-action-panel-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="save_share"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection">
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div>
</div>
<div class="action-panel-control-wrap existing-collections-controls">
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
Choose a collection:
</label>
<select id="collections-action-panel-add-to-existing"
class="action-panel-selector collections-action-add-to-existing"
data-ga-category="save_share"
data-ga-action="select_collection"
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
</select>
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your collection due to an error<br>
<a href="#">Please try again</a>
</div>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="add">
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to Collections' panel"
ref="linksrc=close_collections_panel"
aria-controls="collections-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="bibliography-action-panel"
class="bibliography-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-bibliography-open-panel-enabled="false"
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to My Bibliography
</h3>
<form id="bibliography-action-panel-form"
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-add-to-bibliography-max-amount="100"
data-add-to-bibliography-batch-size="10"
data-bibliography-delegates-url="/list-bibliography-delegates/"
data-add-to-bibliography-url="/add-to-bibliography/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
<input type="hidden" name="csrfmiddlewaretoken" value="3QcQeKVISpmCzpC84Mm8o8f3Ra5rC5v4kDWVRAo4s096tQIYH5ZaSgLHpeNDvG3o">
<div class="action-panel-control-wrap bibliographies-controls">
<div class="choice-group">
<ul class="bibliographies-action-add radio-group-items">
<li>
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/>
<label for="my-bibliography">My Bibliography</label>
</li>
</ul>
</div>
</div>
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your delegates due to an error<br>
<a href="#">Please try again</a>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore>
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to bibliography' panel"
ref="linksrc=close_bibliography_panel"
aria-controls="bibliography-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="mybib"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true"
data-saved-search-open-panel-enabled="false"
data-saved-search-open-panel-url-hash="#open-saved-search-panel">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your saved search
</h2>
<form id="saved-search-action-panel-form"
class="saved-search-action-panel-form action-panel-content action-form"
data-create-saved-search-url="/create-saved-search/"
data-try-search-terms-url="/try-search-term/"
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
<input type="hidden" name="csrfmiddlewaretoken" value="3QcQeKVISpmCzpC84Mm8o8f3Ra5rC5v4kDWVRAo4s096tQIYH5ZaSgLHpeNDvG3o">
<div class="action-panel-control-wrap">
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk">
Name of saved search:
</label>
<input maxlength="200"
type="text"
name="saved-search-name"
id="saved-search-name"
class="saved-search-name"
value=""
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
Search terms:
</label>
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
</div>
<div class="test-search-term-wrap">
<a href="#" class="try-search-term">Test search terms</a>
</div>
<div class="choice-group action-panel-extra-margin-top">
<span class="action-panel-label" id="fieldset-label">
Would you like email updates of new search results?
</span>
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
<ul class="radio-group-items">
<li>
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
</li>
<li>
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
<label for="saved-search-alert-no" class="action-panel-label">No</label>
</li>
</ul>
</fieldset>
</div>
<div class="alert-schedule-wrap">
<div class="action-panel-control-wrap">
<label class="action-panel-label">
Email:
</label>
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
</div>
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="saved-search-frequency" class="action-panel-label">
Frequency:
</label>
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
<option value="monthly">Monthly</option>
<option value="weekly">Weekly</option>
<option value="daily">Daily</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-monthly-additional">
<label for="saved-search-monthly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
<option value="Sunday">The first Sunday</option>
<option value="Monday">The first Monday</option>
<option value="Tuesday">The first Tuesday</option>
<option value="Wednesday">The first Wednesday</option>
<option value="Thursday">The first Thursday</option>
<option value="Friday">The first Friday</option>
<option value="Saturday">The first Saturday</option>
<option value="day">The first day</option>
<option value="weekday">The first weekday</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-weekly-additional">
<label for="saved-search-weekly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
<option value="Sunday">Sunday</option>
<option value="Monday">Monday</option>
<option value="Tuesday">Tuesday</option>
<option value="Wednesday">Wednesday</option>
<option value="Thursday">Thursday</option>
<option value="Friday">Friday</option>
<option value="Saturday">Saturday</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-report" class="action-panel-label">
Report format:
</label>
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
<option value="DocSum">Summary</option>
<option value="DocSumText">Summary (text)</option>
<option value="Abstract">Abstract</option>
<option value="AbstractText">Abstract (text)</option>
<option value="MEDLINE">PubMed</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-amount" class="action-panel-label">
Send at most:
</label>
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
<option value="1">1 item</option>
<option value="5" selected>5 items</option>
<option value="10">10 items</option>
<option value="20">20 items</option>
<option value="50">50 items</option>
<option value="100">100 items</option>
<option value="200">200 items</option>
</select>
</div>
<div>
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox">
Send even when there aren't any new results
</label>
</div>
<div class="action-panel-control-wrap option-text-in-email-wrap">
<label for="saved-search-email-text" class="action-panel-label">
Optional text in email:
</label>
<textarea name="saved-search-email-text"
id="saved-search-email-text"
class="saved-search-email-text"></textarea>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Saving..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Save
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your saved search' panel"
ref="linksrc=close_saved_search_panel"
aria-controls="saved-search-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Create a file for external citation management software
</h2>
<form id="citation-manager-action-panel-form"
class="action-panel-content action-form"
action="/results-export-ids/"
data-by-search-action="/results-export-search-data/"
data-by-ids-action="/results-export-ids/"
method="post"
data-by-search-method="post"
data-by-ids-method="post">
<input type="hidden" name="csrfmiddlewaretoken" value="3QcQeKVISpmCzpC84Mm8o8f3Ra5rC5v4kDWVRAo4s096tQIYH5ZaSgLHpeNDvG3o">
<input name="results-format" type="hidden" value="pubmed"/>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="save">
Create file
</button>
<button class="action-panel-cancel"
aria-label="Close 'Send citations to citation manager' panel"
ref="linksrc=close_citation_manager_panel"
aria-controls="citation-manager-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your RSS Feed
</h2>
<form id="rss-action-panel-form"
class="rss-action-panel-form action-panel-content action-form"
data-create-rss-feed-url="/create-rss-feed-url/"
data-search-form-term-value="">
<input type="hidden" name="csrfmiddlewaretoken" value="3QcQeKVISpmCzpC84Mm8o8f3Ra5rC5v4kDWVRAo4s096tQIYH5ZaSgLHpeNDvG3o">
<div class="action-panel-control-wrap">
<label for="rss-name" class="action-panel-label required-field-asterisk">
Name of RSS Feed:
</label>
<input maxlength="200"
placeholder="Name"
type="text"
name="rss-name"
id="rss-name"
class="rss-name"
value=''
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="rss-limit-wrap">
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="rss-limit" class="action-panel-label">
Number of items displayed:
</label>
<select id="rss-limit" class="no-border-panel-selector rss-limit">
<option value="5">5</option>
<option value="10">10</option>
<option value="15" selected="selected">15</option>
<option value="20">20</option>
<option value="50">50</option>
<option value="100">100</option>
</select>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Creating..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Create RSS
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your RSS' panel"
ref="linksrc=close_rss_panel"
aria-controls="rss-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
<div class="action-panel-control-wrap rss-link-copy-wrap">
<label for="rss-link" class="usa-sr-only">RSS Link</label>
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
<button
type="button"
disabled
class="rss-link-copy-button disabled"
data-ga-category="save_share"
data-ga-action="rss"
data-ga-label="copy">
Copy
</button>
</div>
</form>
</div>
</div>
</div>
</div>
<div class="article-page" id="article-page" data-article-pmid="33806916">
<aside class="page-sidebar">
<div class="inner-wrap">
<div class="full-text-links">
<div class="full-view">
<h3 class="title">
Full text links
</h3>
<div class="full-text-links-list">
<a class="link-item
dialog-focus"
href="https://www.mdpi.com/resolver?pii=jcm10061323"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=False&amp;PrId=6383&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=33806916&amp;db=pubmed&amp;nlmid=101606588"
title="See full text options at MDPI"
data-ga-category="full_text"
data-ga-action="MDPI"
data-ga-label="33806916"
><img src="https://cdn.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--res.mdpi.com-data-pubmed-linkout.png" alt="MDPI full text link"><span class="text">
MDPI
</span></a><a class="link-item
pmc
"
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/33806916/"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=True&amp;PrId=3494&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=33806916&amp;db=pubmed&amp;nlmid=101606588"
title="Free full text at PubMed Central"
data-ga-category="full_text"
data-ga-action="PMC"
data-ga-label="33806916"
><span class="text">
Free PMC article
</span></a>
</div>
</div>
<div class="short-view">
<a href="#" class="full-text-links-button full-text-links-dialog-trigger">
Full text links
</a>
</div>
</div>
<div class="actions-buttons sidebar"><h3 class="title">Actions</h3><div class="inner-wrap"><button class="citation-button citation-dialog-trigger"
aria-label="Open dialog with citation text in different styles"
data-ga-category="save_share"
data-ga-action="cite"
data-ga-label="open"
data-all-citations-url="/33806916/citations/"
data-citation-style="nlm"
data-pubmed-format-link="/33806916/export/"><span class="button-label">Cite</span></button><link type="text/css" href="ncbi-overlay-block/src/overlay-block.css"><div class="collections-button-container" data-article-id="33806916" data-article-db="pubmed"><button class="collections-button collections-dialog-trigger"
aria-label="Save article in MyNCBI collections."
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_button"
data-collections-open-dialog-enabled="false"
data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F33806916%2F%23open-collections-dialog"
data-in-collections="false"><span class="button-label">Collections</span></button><div class="overlay" role="dialog"><div id="collections-action-dialog"
class="dialog collections-dialog"
aria-hidden="true"><div class="title">Add to Collections</div><div class="collections-action-panel action-panel"><form id="collections-action-dialog-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-myncbi-max-collection-name-length="100"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"><input type="hidden" name="csrfmiddlewaretoken" value="3QcQeKVISpmCzpC84Mm8o8f3Ra5rC5v4kDWVRAo4s096tQIYH5ZaSgLHpeNDvG3o"><div class="choice-group" role="radiogroup"><ul class="radio-group-items"><li><input type="radio"
id="collections-action-dialog-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
id="collections-action-dialog-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li></ul></div><div class="controls-wrapper"><div class="action-panel-control-wrap new-collections-controls"><label for="collections-action-dialog-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label><input
type="text"
name="add-to-new-collection"
id="collections-action-dialog-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="collections_button"
data-ga-action="create_collection"
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Preclinical Characterization of the Distribution, Catabolism, and Elimination of a Polatuzumab Vedotin-Piiq (POLIVY<sup>®</sup>) Antibody-Drug Conjugate in Sprague Dawley Rats
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<div class="abstract" id="abstract">
<h2 class="title">
Abstract
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<p>
Polatuzumab vedotin (or POLIVY<sup>®</sup>), an antibody-drug conjugate (ADC) composed of a polatuzumab monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a cleavable dipeptide linker, has been approved by the United States Food and Drug Administration (FDA) for the treatment of diffuse large B-cell lymphoma (DLBCL). To support the clinical development of polatuzumab vedotin, we characterized the distribution, catabolism/metabolism, and elimination properties of polatuzumab vedotin and its unconjugated MMAE payload in Sprague Dawley rats. Several radiolabeled probes were developed to track the fate of different components of the ADC, with <sup>125</sup>I and <sup>111</sup>In used to label the antibody component and <sup>3</sup>H to label the MMAE payload of the ADC. Following a single intravenous administration of the radiolabeled probes into normal or bile-duct cannulated rats, blood, various tissues, and excreta samples were collected over 7-14 days post-dose and analyzed for radioactivity and to characterize the metabolites/catabolites. The plasma radioactivity of polatuzumab vedotin showed a biphasic elimination profile similar to that of unconjugated polatuzumab but different from unconjugated radiolabeled MMAE, which had a fast clearance. The vast majority of the radiolabeled MMAE in plasma remained associated with antibodies, with a minor fraction as free MMAE and MMAE-containing catabolites. Similar to unconjugated mAb, polatuzumab vedotin showed a nonspecific distribution to multiple highly perfused organs, including the lungs, heart, liver, spleen, and kidneys, where the ADC underwent catabolism to release MMAE and other MMAE-containing catabolites. Both polatuzumab vedotin and unconjugated MMAE were mainly eliminated through the biliary fecal route (&gt;90%) and a small fraction (&lt;10%) was eliminated through renal excretion in the form of catabolites/metabolites, among which, MMAE was identified as the major species, along with several other minor species. These studies provided significant insight into ADC's absorption, distribution, metabolism, and elimination (ADME) properties, which supports the clinical development of POLIVY.
</p>
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<p>
<strong class="sub-title">
Keywords:
</strong>
antibodydrug conjugate (ADC); distribution, catabolism, and elimination (DME); mass balance; monomethyl auristatin E (MMAE); polatuzumab vedotin (POLIVY).
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Conflict of interest statement
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<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">The authors are Genentech employees at the time of conducting these studies and declare no conflict of interest.</p>
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<div class="figures" id="figures">
<h2 class="title">
Figures
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data-image-width="724"
data-image-height="148"
data-image-alt="Figure 1"
data-pmc-id="PMC8004598"
data-figure-id="jcm-10-01323-f001">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-0"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1413/8004598/a4fab9babfad/jcm-10-01323-g001.gif"
alt="Figure 1" />
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<strong class="figure-label">
<p> Figure 1 </p>
</strong>
<div class="figure-caption-contents"><p> Structure of [ <sup> 3 </sup> H]-monomethyl… </p></div>
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</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 1 </p>
</strong>
<div class="figure-caption-contents"><p> Structure of [ <sup> 3 </sup> H]-monomethyl auristatin E (MMAE)-polatuzumab vedotin (drug-to-antibody ratio (DAR) of… </p></div>
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<figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 1
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<div class="figure-caption-contents">Structure of [<sup>3</sup>H]-monomethyl auristatin E (MMAE)-polatuzumab vedotin (drug-to-antibody ratio (DAR) of 3.4) and the location of the radiolabeled <sup>3</sup>H on the MMAE.</div>
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</figure>
<figure class="figure-item "
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data-image-width="765"
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data-image-alt="Figure 2"
data-pmc-id="PMC8004598"
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<img class="figure-thumb" itemprop="thumbnail"
id="article-image-1"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1413/8004598/28b28b78d61c/jcm-10-01323-g002.gif"
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<strong class="figure-label">
<p> Figure 2 </p>
</strong>
<div class="figure-caption-contents"><p> The systemic pharmacokinetics (PK) and… </p></div>
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<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 2 </p>
</strong>
<div class="figure-caption-contents"><p> The systemic pharmacokinetics (PK) and tissue biodistribution of unconjugated [ <sup> 3 </sup> H]-MMAE following… </p></div>
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<figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 2
</strong>
<div class="figure-caption-contents">The systemic pharmacokinetics (PK) and tissue biodistribution of unconjugated [<sup>3</sup>H]-MMAE following a single intravenous (IV) administration. (<b>A</b>) Radioactivity of [<sup>3</sup>H]-MMAE (as a percentage of the injected dose) from the whole blood, plasma, and cell pellets in rats up to 144 h post administration. A six- to eight-fold higher level of radioactivity was observed throughout the study in the cell pellets isolated from blood compared to the plasma, suggesting a strong partition to red blood cells. (<b>B</b>) Radioactivity of [<sup>3</sup>H]-MMAE from blood and multiple tissues isolated from rats at various time points post IV administration. The data are represented as the mean ± standard deviation (SD). <i>n</i> = 3 per time point. S. Intestine: small intestine; L. Intestine: large intestine.</div>
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<img class="figure-thumb" itemprop="thumbnail"
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src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1413/8004598/2e63a6b83e0f/jcm-10-01323-g003.gif"
alt="Figure 3" />
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<strong class="figure-label">
<p> Figure 3 </p>
</strong>
<div class="figure-caption-contents"><p> The route of elimination of… </p></div>
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<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 3 </p>
</strong>
<div class="figure-caption-contents"><p> The route of elimination of unconjugated [ <sup> 3 </sup> H]-MMAE in rats following a… </p></div>
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<figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 3
</strong>
<div class="figure-caption-contents">The route of elimination of unconjugated [<sup>3</sup>H]-MMAE in rats following a single IV administration. The total <sup>3</sup>H radioactivity in feces and urine samples was collected through the study, while bile samples were collected in a separate set of bile-duct-cannulated rats. The data are represented as the mean ± SD. <i>n</i> = 6 per time point up to 24 h (including 24 h), and <i>n</i> = 3 per time point beyond 24 h to the end of the study.</div>
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role="button"
data-image-width="785"
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data-image-alt="Figure 4"
data-pmc-id="PMC8004598"
data-figure-id="jcm-10-01323-f004">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-3"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1413/8004598/cca1875d5ead/jcm-10-01323-g004.gif"
alt="Figure 4" />
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<strong class="figure-label">
<p> Figure 4 </p>
</strong>
<div class="figure-caption-contents"><p> Structure of MMAE and its… </p></div>
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<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 4 </p>
</strong>
<div class="figure-caption-contents"><p> Structure of MMAE and its metabolites identified, with the possible biotransformations in the… </p></div>
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<figcaption id="figure-caption-3" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 4
</strong>
<div class="figure-caption-contents">Structure of MMAE and its metabolites identified, with the possible biotransformations in the rat bile samples dosed with [<sup>3</sup>H]-MMAE.</div>
</figcaption>
</figure>
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aria-describedby="figure-caption-4"
role="button"
data-image-width="773"
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data-image-alt="Figure 5"
data-pmc-id="PMC8004598"
data-figure-id="jcm-10-01323-f005">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-4"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1413/8004598/7ea1295a665e/jcm-10-01323-g005a.gif"
alt="Figure 5" />
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<strong class="figure-label">
<p> Figure 5 </p>
</strong>
<div class="figure-caption-contents"><p> Profiles of the blood radioactivity… </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 5 </p>
</strong>
<div class="figure-caption-contents"><p> Profiles of the blood radioactivity levels vs. time of radiolabeled polatuzumab vedotin following… </p></div>
</div>
<figcaption id="figure-caption-4" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 5
</strong>
<div class="figure-caption-contents">Profiles of the blood radioactivity levels vs. time of radiolabeled polatuzumab vedotin following a single IV administration. (<b>A</b>) Radioactivity of [<sup>125</sup>I]-polatuzumab vedotin (as a percentage of the injected dose) comparing with [<sup>125</sup>I]-polatuzumab antibodies in plasma in rats at tracer (≈3 ug/kg) and tracer plus 10 mg/kg dose levels up to 14 days post administration. The data are represented as the mean ± SD. <i>n</i> = 3 per time point. (<b>B</b>) Radioactivity of [<sup>3</sup>H]-MMAE-polatuzumab vedotin (as a percentage of the injected dose) from the whole blood, plasma, and cell pellets in rats up to 14 days post administration. The data are represented as the mean ± SD. <i>n</i> = 3 per time point. (<b>C</b>) Plasma from the rats dosed with [<sup>3</sup>H]-MMAE-polatuzumab vedotin were further processed using organic solvent precipitation, which showed that most of the radioactivity was in the precipitable fraction, suggesting that the MMAE payload was still conjugated to the antibodies in the plasma.</div>
</figcaption>
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role="button"
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data-figure-id="jcm-10-01323-f005">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-5"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1413/8004598/7ea1295a665e/jcm-10-01323-g005a.gif"
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<div class="caption-wrap">
<strong class="figure-label">
<p> Figure 5 </p>
</strong>
<div class="figure-caption-contents"><p> Profiles of the blood radioactivity… </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 5 </p>
</strong>
<div class="figure-caption-contents"><p> Profiles of the blood radioactivity levels vs. time of radiolabeled polatuzumab vedotin following… </p></div>
</div>
<figcaption id="figure-caption-5" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 5
</strong>
<div class="figure-caption-contents">Profiles of the blood radioactivity levels vs. time of radiolabeled polatuzumab vedotin following a single IV administration. (<b>A</b>) Radioactivity of [<sup>125</sup>I]-polatuzumab vedotin (as a percentage of the injected dose) comparing with [<sup>125</sup>I]-polatuzumab antibodies in plasma in rats at tracer (≈3 ug/kg) and tracer plus 10 mg/kg dose levels up to 14 days post administration. The data are represented as the mean ± SD. <i>n</i> = 3 per time point. (<b>B</b>) Radioactivity of [<sup>3</sup>H]-MMAE-polatuzumab vedotin (as a percentage of the injected dose) from the whole blood, plasma, and cell pellets in rats up to 14 days post administration. The data are represented as the mean ± SD. <i>n</i> = 3 per time point. (<b>C</b>) Plasma from the rats dosed with [<sup>3</sup>H]-MMAE-polatuzumab vedotin were further processed using organic solvent precipitation, which showed that most of the radioactivity was in the precipitable fraction, suggesting that the MMAE payload was still conjugated to the antibodies in the plasma.</div>
</figcaption>
</figure>
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data-image-height="645"
data-image-alt="Figure 6"
data-pmc-id="PMC8004598"
data-figure-id="jcm-10-01323-f006">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-6"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1413/8004598/0fa7ae8a67a1/jcm-10-01323-g006a.gif"
alt="Figure 6" />
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<strong class="figure-label">
<p> Figure 6 </p>
</strong>
<div class="figure-caption-contents"><p> The tissue distribution of radiolabeled… </p></div>
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</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 6 </p>
</strong>
<div class="figure-caption-contents"><p> The tissue distribution of radiolabeled polatuzumab vedotin and unconjugated polatuzumab antibody after a… </p></div>
</div>
<figcaption id="figure-caption-6" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 6
</strong>
<div class="figure-caption-contents">The tissue distribution of radiolabeled polatuzumab vedotin and unconjugated polatuzumab antibody after a single dose via IV administration in rats. (<b>A</b>) The tissue and blood radioactivity from intact (<sup>125</sup>I radioactivity—solid bar) and catabolized (subtract <sup>125</sup>I radioactivity from <sup>111</sup>In radioactivity—open bar) polatuzumab vedotin dosed at the tracer (≈3 μg/kg) level up to 14 days post administration. (<b>B</b>) The tissues and blood radioactivity from intact (<sup>125</sup>I radioactivity—solid bar) and catabolized (<sup>111</sup>In subtracted with <sup>125</sup>I radioactivity—open bar) unconjugated polatuzumab antibody dosed at the tracer (≈34 μg/kg) level up to 14 days post administration. (<b>C</b>) The tissues and plasma radioactivity from conjugated (<sup>3</sup>H precipitated radioactivity—solid bar) and deconjugated (<sup>3</sup>H soluble radioactivity—open bar) [<sup>3</sup>H]-MMAE-polatuzumab vedotin dosed at 10 mg/kg up to 14 days post administration. A higher distribution of polatuzumab vedotin was observed in highly perfused tissues, such as the liver, spleen, and kidneys, and resulted in higher catabolism. The data are represented as the mean ± SD (except in (<b>C</b>) where only the mean is reported). <i>n</i> = 3 per time point. S. Intestine: small intestine; L. Intestine: large intestine; B. Marrows: bone marrows; A. gland: adrenal glands; DRG: dorsal root ganglions; Sc. Nerve: sciatic nerve.</div>
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<p> Figure 6 </p>
</strong>
<div class="figure-caption-contents"><p> The tissue distribution of radiolabeled… </p></div>
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<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 6 </p>
</strong>
<div class="figure-caption-contents"><p> The tissue distribution of radiolabeled polatuzumab vedotin and unconjugated polatuzumab antibody after a… </p></div>
</div>
<figcaption id="figure-caption-7" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 6
</strong>
<div class="figure-caption-contents">The tissue distribution of radiolabeled polatuzumab vedotin and unconjugated polatuzumab antibody after a single dose via IV administration in rats. (<b>A</b>) The tissue and blood radioactivity from intact (<sup>125</sup>I radioactivity—solid bar) and catabolized (subtract <sup>125</sup>I radioactivity from <sup>111</sup>In radioactivity—open bar) polatuzumab vedotin dosed at the tracer (≈3 μg/kg) level up to 14 days post administration. (<b>B</b>) The tissues and blood radioactivity from intact (<sup>125</sup>I radioactivity—solid bar) and catabolized (<sup>111</sup>In subtracted with <sup>125</sup>I radioactivity—open bar) unconjugated polatuzumab antibody dosed at the tracer (≈34 μg/kg) level up to 14 days post administration. (<b>C</b>) The tissues and plasma radioactivity from conjugated (<sup>3</sup>H precipitated radioactivity—solid bar) and deconjugated (<sup>3</sup>H soluble radioactivity—open bar) [<sup>3</sup>H]-MMAE-polatuzumab vedotin dosed at 10 mg/kg up to 14 days post administration. A higher distribution of polatuzumab vedotin was observed in highly perfused tissues, such as the liver, spleen, and kidneys, and resulted in higher catabolism. The data are represented as the mean ± SD (except in (<b>C</b>) where only the mean is reported). <i>n</i> = 3 per time point. S. Intestine: small intestine; L. Intestine: large intestine; B. Marrows: bone marrows; A. gland: adrenal glands; DRG: dorsal root ganglions; Sc. Nerve: sciatic nerve.</div>
</figcaption>
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data-image-width="749"
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data-pmc-id="PMC8004598"
data-figure-id="jcm-10-01323-f007">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-8"
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<strong class="figure-label">
<p> Figure 7 </p>
</strong>
<div class="figure-caption-contents"><p> The route of elimination of… </p></div>
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</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 7 </p>
</strong>
<div class="figure-caption-contents"><p> The route of elimination of [ <sup> 3 </sup> H]-MMAE-polatuzumab vedotin in rats following a… </p></div>
</div>
<figcaption id="figure-caption-8" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 7
</strong>
<div class="figure-caption-contents">The route of elimination of [<sup>3</sup>H]-MMAE-polatuzumab vedotin in rats following a single IV administration. The total <sup>3</sup>H radioactivity in the feces and urine samples collected through the study. Bile samples were collected in a separate set of bile-duct-cannulated rats. The acetonitrile (ACN) precipitation of urine and feces samples showed that the majority (&gt;80%) of radioactivity was in the ACN-soluble fraction, suggesting that [<sup>3</sup>H]-MMAE-polatuzumab vedotin was eliminated mainly as [<sup>3</sup>H]-MMAE or [<sup>3</sup>H]-containing small molecule catabolites. Similarly, the acetonitrile precipitation of bile samples showed &gt;95% of the radioactivity in the soluble fraction. The data are represented as the mean ± SD. For the urine and feces data, <i>n</i> = 6 per time point up to 7 days (including at day 7), <i>n</i> = 3 per time point from beyond 7 days to the end of the study. <i>n</i> = 6 per time point for the bile samples.</div>
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aria-describedby="figure-caption-9"
role="button"
data-image-width="744"
data-image-height="454"
data-image-alt="Figure 8"
data-pmc-id="PMC8004598"
data-figure-id="jcm-10-01323-f008">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-9"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1413/8004598/45421997cee0/jcm-10-01323-g008.gif"
alt="Figure 8" />
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<strong class="figure-label">
<p> Figure 8 </p>
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<div class="figure-caption-contents"><p> Structure of the catabolites identified,… </p></div>
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<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
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<p> Figure 8 </p>
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<div class="figure-caption-contents"><p> Structure of the catabolites identified, with the possible biotransformations in rat bile samples… </p></div>
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<figcaption id="figure-caption-9" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 8
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<div class="figure-caption-contents">Structure of the catabolites identified, with the possible biotransformations in rat bile samples dosed with [<sup>3</sup>H]-MMAE-polatuzumab vedotin.</div>
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