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Denis R. Beckford Vera, Christof C. Smith, Lisa M. Bixby, Dylan M. Glatt, Stuart S. Dunn, Ryoichi Saito, William Y. Kim, Jonathan S. Serody, Benjamin G. Vincent, Matthew C. Parrott
Immuno-PET imaging of tumor-infiltrating lymphocytes using zirconium-89 radiolabeled anti-CD3 antibody in immune-competent mice bearing syngeneic tumors
www.plosone.org
www.plosone.org
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1 TL
-0.004 Tc
0 0 Td
(has)Tj
1.542 0 Td
(the)Tj
1.4683 0 Td
(potential)Tj
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(to)Tj
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(non-invasively)Tj
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(detect)Tj
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(helper/regulatory)Tj
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(and)Tj
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(cytotoxic)Tj
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(T-cell)Tj
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(limitation)Tj
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(antibodies)Tj
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(CD4)Tj
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(information)Tj
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(obtained)Tj
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(regarding)Tj
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(the)Tj
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(response.)Tj
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(inclusive)Tj
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(protein)Tj
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(expressed)Tj
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(cells)Tj
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(T-cell)Tj
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(marker)Tj
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(which)Tj
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(development.)Tj
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(specificity)Tj
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(lineage)Tj
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(development)Tj
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(make)Tj
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(CD3)Tj
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(a)Tj
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(rational)Tj
3.3279 0 Td
(candidate)Tj
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(detecting)Tj
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(populations)Tj
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(in)Tj
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(vivo.)Tj
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(specific)Tj
3.1918 0 Td
(for)Tj
1.3833 0 Td
(CD3)Tj
2.0977 0 Td
(can)Tj
1.627 0 Td
(have)Tj
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(substantial)Tj
4.5014 0 Td
(effects)Tj
2.7269 0 Td
(on)Tj
1.2756 0 Td
(the)Tj
1.4683 0 Td
(function)Tj
3.6283 0 Td
(of)Tj
1.0148 0 Td
(CD4)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 526.6204 607.8614 cm
BT
/F6 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(+)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 533.1401 603.3826 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(and)Tj
1.7347 0 Td
(CD8)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 569.1968 607.8614 cm
BT
/F6 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(+)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 590.4 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(T)Tj
0.8277 0 Td
(cells)Tj
1.9218 0 Td
(in)Tj
1.0375 0 Td
(vivo,)Tj
2.126 0 Td
(including)Tj
4.0422 0 Td
(induced)Tj
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(T)Tj
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(cell)Tj
1.559 0 Td
(activation)Tj
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(and)Tj
1.7291 0 Td
(expansion)Tj
4.2916 0 Td
([)Tj
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(20)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(22)Tj
0 g
(].)Tj
3.5433 0 Td
(Furthermore,)Tj
-29.5311 -1.2982 Td
(administration)Tj
6.1681 0 Td
(of)Tj
1.0148 0 Td
(high)Tj
2.0069 0 Td
(dose)Tj
2.0409 0 Td
(anti-CD3)Tj
3.9912 0 Td
(mAb)Tj
2.2337 0 Td
(can)Tj
1.6271 0 Td
(preferentially)Tj
5.5332 0 Td
(deplete)Tj
3.0784 0 Td
(T)Tj
0.8333 0 Td
(cells)Tj
/F12 1 Tf
1.9163 0 Td
[()12()]TJ
1.0147 0 Td
[()-13()15()3()]TJ
/F6 1 Tf
1.8199 0 Td
([)Tj
0.83 0.64 0.02 0 k
(9)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.2642 0 Td
(22)Tj
0 g
(].)Tj
-34.5427 -1.3039 Td
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4.3936 0 Td
(while)Tj
2.3641 0 Td
(anti-CD3)Tj
3.9968 0 Td
(mAb)Tj
2.228 0 Td
(can)Tj
1.6271 0 Td
(be)Tj
1.1509 0 Td
(used)Tj
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(tag)Tj
1.4173 0 Td
(T)Tj
0.8334 0 Td
(cells,)Tj
2.1429 0 Td
(its)Tj
1.1509 0 Td
(effects)Tj
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2.7212 0 Td
[()12()]TJ
1.0148 0 Td
[()-13()15()3()]TJ
/F6 1 Tf
1.8199 0 Td
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1.4513 0 Td
(variable)Tj
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(and)Tj
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(depend)Tj
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(on)Tj
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(dosage,)Tj
3.1634 0 Td
(isotype,)Tj
3.2768 0 Td
(surface)Tj
3.0501 0 Td
(antigen)Tj
3.2031 0 Td
(density)Tj
3.1011 0 Td
(on)Tj
1.2756 0 Td
(target)Tj
2.5115 0 Td
(T)Tj
0.8277 0 Td
(cells,)Tj
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(and)Tj
1.7291 0 Td
(antigen)Tj
3.2032 0 Td
(internaliza-)Tj
-31.9519 -1.2983 Td
(tion/modulation)Tj
6.8541 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(target)Tj
2.5115 0 Td
(cell)Tj
1.559 0 Td
(population)Tj
4.5921 0 Td
([)Tj
0.83 0.64 0.02 0 k
(20)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(25)Tj
0 g
(].)Tj
3.5433 0 Td
(Previously,)Tj
4.6148 0 Td
(zirconium-89)Tj
5.6693 0 Td
(labeled)Tj
3.0273 0 Td
(anti-)Tj
-34.8545 -1.3039 Td
(CD3)Tj
2.0919 0 Td
(indicated)Tj
3.9401 0 Td
(a)Tj
0.652 0 Td
(strong)Tj
2.7723 0 Td
(correlation)Tj
4.6204 0 Td
(between)Tj
3.5263 0 Td
(anti-CTLA-4treated)Tj
8.7363 0 Td
(mice)Tj
2.1543 0 Td
(and)Tj
1.7292 0 Td
(tumor)Tj
2.7439 0 Td
(volume)Tj
-32.9667 -1.2982 Td
([)Tj
0.83 0.64 0.02 0 k
(26)Tj
0 g
(].)Tj
2.0749 0 Td
(However,)Tj
4.0762 0 Td
(the)Tj
1.4683 0 Td
(immunological)Tj
6.3042 0 Td
(effects)Tj
2.7213 0 Td
(of)Tj
1.0148 0 Td
(radiolabeled)Tj
5.1363 0 Td
(anti-CD3)Tj
3.9969 0 Td
(mAb)Tj
2.228 0 Td
(at)Tj
0.9524 0 Td
(the)Tj
1.4683 0 Td
(doses)Tj
2.4038 0 Td
(used)Tj
2.0579 0 Td
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-35.9033 -1.2983 Td
(PET)Tj
1.9558 0 Td
(imaging)Tj
3.4866 0 Td
(are)Tj
1.4514 0 Td
(still)Tj
1.6384 0 Td
(unknown.)Tj
4.3086 0 Td
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0.8561 0 Td
(is)Tj
0.8504 0 Td
(therefore)Tj
3.8551 0 Td
(important)Tj
4.2802 0 Td
(to)Tj
1.0262 0 Td
(elucidate)Tj
3.787 0 Td
(the)Tj
1.474 0 Td
(immunomodulatory)Tj
-28.9698 -1.2983 Td
(effects)Tj
2.7269 0 Td
(of)Tj
1.0148 0 Td
(this)Tj
1.6724 0 Td
(novel)Tj
2.3981 0 Td
(compound)Tj
4.5978 0 Td
(to)Tj
1.0261 0 Td
(determine)Tj
4.3256 0 Td
(if)Tj
0.771 0 Td
(it)Tj
0.7881 0 Td
(has)Tj
1.542 0 Td
(the)Tj
1.4683 0 Td
(potential)Tj
3.7644 0 Td
(to)Tj
1.0205 0 Td
(polarize)Tj
3.4016 0 Td
(T)Tj
0.8333 0 Td
(cells)Tj
1.9162 0 Td
(toward)Tj
3.0444 0 Td
(an)Tj
-36.3115 -1.3039 Td
(activated)Tj
3.7813 0 Td
(and)Tj
1.7292 0 Td
(potentially)Tj
4.4617 0 Td
(anti-tumor)Tj
4.6431 0 Td
(phenotype)Tj
4.439 0 Td
(when)Tj
2.4038 0 Td
(used)Tj
2.0579 0 Td
(as)Tj
1.0148 0 Td
(a)Tj
0.652 0 Td
(component)Tj
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(of)Tj
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(immuno-PET)Tj
-31.0108 -1.2983 Td
(imaging.)Tj
1.1962 -1.2982 Td
(We)Tj
1.61 0 Td
(hypothesized)Tj
5.4709 0 Td
(that)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 300.5858 451.8425 cm
BT
/F6 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(89)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 307.6724 447.4204 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Zr)Tj
1.1905 0 Td
(radiolabeled)Tj
5.1363 0 Td
(anti-CD3)Tj
3.9969 0 Td
(mAb)Tj
2.228 0 Td
(has)Tj
1.542 0 Td
(potential)Tj
3.7587 0 Td
(for)Tj
1.389 0 Td
(immuno-PET)Tj
-30.0073 -1.3039 Td
(detection)Tj
3.9345 0 Td
(of)Tj
1.0148 0 Td
(tumor-infiltrating)Tj
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(T)Tj
0.8277 0 Td
(lymphocytes)Tj
5.2554 0 Td
(in)Tj
1.0375 0 Td
(mice)Tj
2.1543 0 Td
(bearing)Tj
3.2315 0 Td
(syngeneic)Tj
4.1385 0 Td
(tumors)Tj
3.1068 0 Td
(without)Tj
-32.0993 -1.2982 Td
(changing)Tj
3.9005 0 Td
(overall)Tj
2.9026 0 Td
(lymphocyte)Tj
4.8925 0 Td
(numbers)Tj
3.7757 0 Td
(or)Tj
1.0999 0 Td
(viability.)Tj
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Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 391.011 cm
BT
/F2 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Results)Tj
ET
Q
q
1 j
1 J
0 w
8.9997 0 0 7.999 200.0125 378.3118 cm
BT
/F13 1 Tf
1 TL
-0.0044 Tc
0 0 Td
(89)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 208.9133 372.9826 cm
BT
/F13 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Zr-DFO-anti-CD3)Tj
7.9039 0 Td
(reagent)Tj
3.3402 0 Td
(generation)Tj
4.7009 0 Td
(and)Tj
1.7952 0 Td
(evaluation)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 355.9748 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Full)Tj
1.7688 0 Td
(details)Tj
2.7779 0 Td
(of)Tj
1.0148 0 Td
(DFO-conjugation,)Tj
7.5855 0 Td
(radiolabeling)Tj
5.4651 0 Td
(and)Tj
1.7348 0 Td
(subsequent)Tj
4.6998 0 Td
(chemical)Tj
3.7871 0 Td
(analysis)Tj
3.3278 0 Td
(can)Tj
1.6271 0 Td
(be)Tj
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(found)Tj
-34.9396 -1.2982 Td
(in)Tj
1.0318 0 Td
(the)Tj
1.474 0 Td
(supplementary)Tj
6.1624 0 Td
(information)Tj
5.074 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(S1)Tj
1.5137 0 Td
(File)Tj
0 g
(\).)Tj
2.2507 0 Td
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3.0727 0 Td
(the)Tj
1.4741 0 Td
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5.0002 0 Td
(reaction)Tj
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(between)Tj
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(murine)Tj
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(anti-CD3)Tj
3.9911 0 Td
(mAb)Tj
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(and)Tj
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(DFO)Tj
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(yielded)Tj
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(1.1)Tj
1.3947 0 Td
(chelating)Tj
3.8551 0 Td
(group)Tj
2.6078 0 Td
(per)Tj
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(protein)Tj
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(molecule)Tj
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(based)Tj
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(on)Tj
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(MALDI-)Tj
-33.4032 -1.2982 Td
(TOF)Tj
2.1032 0 Td
(mass)Tj
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(spectrometry)Tj
5.4936 0 Td
(\([m/z)Tj
2.4604 0 Td
(\(DFO-anti-CD3\)m/z)Tj
9.1162 0 Td
(\(anti-CD3\)]/)Tj
5.3404 0 Td
(M.W)Tj
2.3074 0 Td
(\(DFO\))Tj
2.9083 0 Td
(=)Tj
0.7994 0 Td
(148438)Tj
-32.7229 -1.304 Td
(147606/752)Tj
4.8302 0 Td
(=)Tj
0.7993 0 Td
(1.1\).)Tj
1.9616 0 Td
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1.7801 0 Td
(DFO-anti-CD3)Tj
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(was)Tj
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(isolated)Tj
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1.7348 0 Td
(purified)Tj
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(chemical)Tj
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(purity)Tj
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(higher)Tj
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(98%.)Tj
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5.5842 0 Td
(SDS-PAGE)Tj
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(for)Tj
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(both)Tj
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(DFO-anti-CD3)Tj
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(unmodified)Tj
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(bands)Tj
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(apparent)Tj
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(molecular)Tj
4.218 0 Td
(weights)Tj
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(~150kDa.)Tj
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(SDS-PAGE)Tj
4.7905 0 Td
(showed)Tj
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(modest)Tj
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(apparent)Tj
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(molecular)Tj
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(weight)Tj
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(the)Tj
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(heavy)Tj
-35.24 -1.2983 Td
(chains)Tj
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(of)Tj
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(the)Tj
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(unmodified)Tj
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(further)Tj
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(confirmed)Tj
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(the)Tj
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(low)Tj
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(degree)Tj
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(DFO)Tj
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(conjugation)Tj
5.0059 0 Td
(to)Tj
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(determined)Tj
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(by)Tj
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(MALDI-TOF-MS.)Tj
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ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 531.8929 243.4393 cm
BT
/F6 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(89)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 538.9795 239.0173 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Zr-DFO-)Tj
-33.8964 -1.3039 Td
(mAb)Tj
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(conjugates)Tj
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(were)Tj
2.1203 0 Td
(isolated)Tj
3.2881 0 Td
(using)Tj
2.3868 0 Td
(size)Tj
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(exclusion)Tj
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(chromatography)Tj
6.8768 0 Td
(\(SEC\))Tj
2.6079 0 Td
(with)Tj
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(radiolabeling)Tj
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